JP2020152649A - Method for producing heterocyclic compound - Google Patents

Abstract

To provide a production method suitable for industrial production of a compound (A).SOLUTION: A compound (A) or a salt thereof is produced in an increased total yield and at low cost, with a reduced number of steps, and without requiring cryogenic reaction conditions or complex operation such as column purification or chiral column purification [where each symbol is as described in the specifications].SELECTED DRAWING: None

Description

The present invention relates to a method for producing a heterocyclic compound.

(Background of invention)
Has excellent RORγt inhibitory effect, psoriasis, inflammatory bowel disease (IBD), ulcerative colitis (UC), Crohn's disease (CD), rheumatoid arthritis, polysclerosis, uveitis, asthma, tonicity The compound (A) shown below is described in Patent Document 1 as a compound useful as a prophylactic or therapeutic agent for spondylitis, systemic erythematosus (SLE) and the like.

WO 2016/002968 A1

In Patent Document 1, the compound (A) is tert-butyl (S) -5-((7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl) carbamoyl) -2. -Methoxy-7,8-dihydro-1,6-naphthylidine-6 (5H) -carboxylate (Compound (10)) and cis-3- (2- (tert-butoxy) -2-oxoethyl) cyclobutanecarboxylic acid ( It is produced in 12 steps (excluding sub-steps) using the free form of compound (18) as a key intermediate. Among these steps, there are steps that require cryogenic reaction conditions, complicated operations such as column purification and chiral column purification, and the total yield is as low as 3.6%.

An object of the present invention is to provide a novel production method and a novel intermediate suitable for industrial production of compound (A).

As a result of diligent studies to solve the above problems, the present inventors
(i) A route for producing compound (10) using compound (1) or a salt thereof as a starting material and producing compound (18) ((S) -1-phenethylamine salt) using compound (12) as a starting material. New routes including (Scheme 1), and
(ii) Compound (10) is produced using compound (20) or a salt thereof and compound (30) or a salt thereof as starting materials, respectively, and compound (36) or a salt thereof is used as a starting material for compound (18) (( S) A new route (Scheme 2) containing a route for producing -1-phenethylamine salt)
However, the number of steps is shorter, and the compound (A) or a salt thereof can be produced inexpensively with a higher overall yield without requiring extremely low temperature reaction conditions or complicated operations such as column purification and chiral column purification. The heading has led to the completion of the present invention.

That is, the present invention relates to the following.
[1] A method for producing compound (A) or a salt thereof, which comprises the steps shown in Scheme 1 below:

(In the formula, Me indicates methyl, Et indicates ethyl, Boc indicates tert-butoxycarbonyl, Bn indicates benzyl, and t-Bu indicates tert-butyl.)
Step 1: A step of reacting a Grineer reagent prepared from compound (1) or a salt thereof with diethyl oxalate to obtain compound (2) or a salt thereof;
Step 2: A step of subjecting compound (2) or a salt thereof to an amidation reaction using ammonia to obtain compound (3) or a salt thereof;
Step 3: A step of subjecting compound (3) or a salt thereof to a vinylization reaction to obtain compound (4) or a salt thereof;
Step 4: A step of subjecting compound (4) or a salt thereof to a cyclization reaction using ammonia to obtain compound (5) or a salt thereof;
Step 5: A step of subjecting compound (5) or a salt thereof to an asymmetric reduction reaction to obtain compound (6) or a salt thereof;
Step 6: A step of subjecting compound (6) or a salt thereof to a t-butoxycarbonyl (Boc) conversion reaction to obtain compound (7) or a salt thereof;
Step 7: A step of subjecting compound (8) to a halogen exchange reaction to obtain compound (9);
Step 8: A step of reacting compound (7) or a salt thereof with compound (9) to obtain compound (10) or a salt thereof;
Step 9: A step of subjecting compound (10) or a salt thereof to a de-Boc reaction to obtain compound (11) or a salt thereof;
Step 10: A step of subjecting compound (12) or a salt thereof to a benzyl esterification reaction to obtain compound (13);
Step 11: A step of reacting compound (13) with Meldrum's acid to obtain compound (14);
Step 12: A step of subjecting compound (14) to a reduction reaction using a reducing agent to obtain compound (15);
Step 13: A step of reacting compound (15) with t-butanol to obtain compound (16);
Step 14: A step of subjecting compound (16) to a catalytic reduction reaction to obtain compound (17) or a salt thereof;
Step 15: A step of subjecting compound (17) or a salt thereof to salt formation with (S) -1-phenethylamine to obtain compound (18);
Step 16: Reacting compound (11) or a salt thereof with compound (18) to obtain compound (19) or a salt thereof; and Step 17: subjecting compound (19) or a salt thereof to an acid hydrolysis reaction. The step of obtaining compound (A) or a salt thereof.
[2] A method for producing compound (A) or a salt thereof, which comprises the steps shown in Scheme 2 below:

(In the formula, Me indicates methyl, Et indicates ethyl, Boc indicates tert-butoxycarbonyl, Bn indicates benzyl, and t-Bu indicates tert-butyl.)
Step 18: A step of subjecting compound (20) or a salt thereof to a t-butoxycarbonyl (Boc) conversion reaction to obtain compound (21);
Step 19: A step of reacting compound (21) with compound (22) or a salt thereof to obtain compound (23) or a salt thereof;
Step 20: A step of subjecting compound (23) or a salt thereof to a de-Boc reaction to obtain compound (24) or a salt thereof;
Step 21: A step of subjecting compound (24) or a salt thereof to a cyclization reaction using ethyl glyoxylate to obtain compound (25) or a salt thereof;
Step 22: The step of subjecting compound (25) or a salt thereof to a t-butoxycarbonyl (Boc) conversion reaction to obtain compound (26) or a salt thereof;
Step 23: A step of subjecting compound (26) or a salt thereof to a methylation reaction to obtain compound (27) or a salt thereof;
Step 24: A step of subjecting compound (27) or a salt thereof to an alkaline hydrolysis reaction to obtain compound (28) or a salt thereof;
Step 25: Compound (28) or a salt thereof is subjected to optical resolution utilizing diastereomeric salt formation with (1S, 2R) -2-amino-1,2-diphenylethanol to give compound (29). Process;
Step 26: A step of converting compound (30) or a salt thereof into acid chloride and then subjecting it to a Friedel-Crafts reaction to obtain compound (31);
Step 27: Reacting compound (31) with benzylamine to obtain compound (32) or a salt thereof;
Step 28: A step of subjecting compound (32) or a salt thereof to a reduction reaction using a reducing agent to obtain compound (33) or a salt thereof;
Step 29: A step of subjecting compound (33) or a salt thereof to a catalytic reduction reaction to obtain compound (34) or a salt thereof;
Step 30: A step of subjecting compound (34) or a salt thereof to salt formation with (+)-camphorsulfonic acid to obtain compound (35);
Step 31: A step of reacting compound (29) with compound (35) to obtain compound (10) or a salt thereof;
Step 32: A step of subjecting compound (10) or a salt thereof to a de-Boc reaction to obtain compound (11) or a salt thereof;
Step 33: A step of subjecting compound (36) or a salt thereof to a catalytic reduction reaction to obtain compound (37) or a salt thereof;
Step 34: A step of subjecting compound (37) or a salt thereof to salt formation with (S) -1-phenethylamine and then fractional crystallization to obtain compound (18);
Step 35: Reacting compound (11) or a salt thereof with compound (18) to obtain compound (19) or a salt thereof; and Step 36: subjecting compound (19) or a salt thereof to an acid hydrolysis reaction. The step of obtaining compound (A) or a salt thereof.

[3] The following compound (2) or a salt thereof.

[4] The following compound (3) or a salt thereof.

[5] The following compound (4) or a salt thereof.

[6] The following compound (5) or a salt thereof.

[7] The following compound (6) or a salt thereof.

[8] The following compound (7) or a salt thereof.

[9] The following compound (9).

[10] The following compound (14).

[11] The following compound (15).

[12] The following compound (16).

[13] The following compound (32) or a salt thereof.

[14] The following compound (33) or a salt thereof.

According to the production method of the present invention, the number of steps is shorter, and the compound (A) is inexpensively produced in a higher overall yield without requiring extremely low temperature reaction conditions or complicated operations such as column purification and chiral column purification. Or the salt can be produced.

(Detailed description of the invention)

The salt of the compound (A) is preferably a pharmacologically acceptable salt, and examples of such a salt include a salt with an inorganic base, a salt with an organic base, a salt with an inorganic acid, and an organic acid. Salts, salts with basic or acidic amino acids.
Preferable examples of salts with inorganic bases include alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt and magnesium salt; aluminum salt; ammonium salt and the like.
Preferable examples of salts with organic bases include trimethylamine, triethylamine, pyridine, picolin, ethanolamine, diethanolamine, triethanolamine, tromethamine [tris (hydroxymethyl) methylamine], tert-butylamine, cyclohexylamine, benzylamine, Examples thereof include salts with dicyclohexylamine, N, N-dibenzylethylenediamine and the like.
Preferable examples of salts with inorganic acids include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like.
Preferable examples of salts with organic acids are formic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid. , P-Toluenesulfonic acid and the like.
Preferable examples of salts with basic amino acids include salts with arginine, lysine, ornithine and the like.
Preferable examples of salts with acidic amino acids include salts with aspartic acid, glutamic acid and the like.

The production method of the present invention will be described below.
The raw materials and reagents used in each step in the following production methods, and the obtained compounds may each form salts. Such a salt is not particularly limited as long as the reaction proceeds, and examples thereof include those similar to the salt of compound (A).

When the compound obtained in each step is a free compound, it can be converted into a target salt by a method known per se. On the contrary, when the compound obtained in each step is a salt, it can be converted into a free form or another kind of salt of interest by a method known per se.

The compound obtained in each step can be used as a reaction solution or as a crude product and then used in the next reaction, or the compound obtained in each step is concentrated from the reaction mixture according to a conventional method. It can be isolated and / or purified by separation means such as crystallization, recrystallization, distillation, solvent extraction, distillation, chromatography and the like.

When a compound of a raw material or a reagent for each step is commercially available, the commercially available product can be used as it is.

Unless otherwise specified, in the reaction of each step, these reactions are carried out without solvent or by dissolving or suspending in a suitable solvent. Specific examples of the solvent include the solvents described in Examples described later, or the following.
Alcohols: Methanol, ethanol, tert-butyl alcohol, 2-methoxyethanol, 1-propanol, 2-propanol, etc .;
Ethers: diethyl ether, diisopropyl ether, cyclopentyl methyl ether, diphenyl ether, tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, etc .;
Aromatic hydrocarbons: chlorobenzene, toluene, xylene, etc .;
Saturated hydrocarbons: cyclohexane, hexane, etc .;
Amides: N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone, etc .;
Halogenated hydrocarbons: dichloromethane, carbon tetrachloride, etc .;
Nitriles: acetonitrile, etc .;
Sulfoxides: Dimethyl sulfoxide, etc .;
Organic bases: pyridine, triethylamine, etc .;
Acid anhydrides: acetic anhydride, etc .;
Organic acids: formic acid, acetic acid, trifluoroacetic acid, etc .;
Inorganic acids: hydrochloric acid, sulfuric acid, etc .;
Esters: ethyl acetate, isopropyl acetate, etc .;
Ketones: acetone, methyl ethyl ketone, etc .;
water.
As the solvent, two or more kinds may be mixed and used in an appropriate ratio.

When a base is used in the reaction of each step, for example, the base shown below or the base described in Examples described later is used.
Inorganic bases: sodium hydroxide, magnesium hydroxide, sodium carbonate, calcium carbonate, sodium hydrogen carbonate, potassium carbonate, etc .;
Organic bases: triethylamine, diethylamine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine, N, N-dimethylaniline, 1,4-diazabicyclo [2.2.2] octane, 1,8-diazabicyclo [5.4. 0] -7-undecene, imidazole, piperidine, etc .;
Metal alkoxides: sodium methoxide, sodium ethoxide, potassium tert-butoxide, sodium tert-butoxide, etc .;
Alkali metal hydrides: sodium hydride, etc .;
Metal amides: sodium amide, lithium diisopropylamide, lithium hexamethyldisilazide, etc .;
Organolithium: n-butyllithium, etc.

When an acid or an acidic catalyst is used in the reaction of each step, for example, the acid or the acidic catalyst shown below, or the acid or the acidic catalyst described in Examples described later is used.
Inorganic acids: hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, phosphoric acid, etc .;
Organic acids: acetic acid, trifluoroacetic acid, citric acid, p-toluenesulfonic acid, 10-camphorsulfonic acid, etc .;
Lewis acid: Boron trifluoride diethyl ether complex, zinc iodide, anhydrous aluminum chloride, anhydrous zinc chloride, anhydrous iron chloride, etc.

Compound (A) or a salt thereof can be produced by the process shown in Scheme 1 below.

(Each group in the formula has the same meaning as above.)

Process 1
In this step, a Grineer reagent prepared from compound (1) or a salt thereof is reacted with diethyl oxalate to obtain compound (2) or a salt thereof.
The reaction for preparing the Grineer reagent from compound (1) or a salt thereof is carried out in a solvent.
The Grineer reagent is prepared by a reaction of compound (1) or a salt thereof with magnesium or an exchange reaction with an alkylmagnesium halide. Examples of the alkylmagnesium halide include isopropylmagnesium chloride, methylmagnesium bromide, tert-butylmagnesium chloride, isopropylmagnesium chloride-lithium chloride complex and the like. The amount of magnesium or alkylmagnesium halide used is generally 0.8-10 mol, preferably 1-2 mol, relative to 1 mol of compound (1) or a salt thereof.
Examples of the solvent include ethers and aromatic hydrocarbons.
The reaction is usually carried out at −80 to 60 ° C., preferably −20 to 30 ° C.
After the preparation of the Grineer reagent, the reaction with diethyl oxalate is subsequently carried out. The reaction is carried out in a solvent.
The amount of diethyl oxalate used is usually 0.8 to 10 mol, preferably 1 to 3 mol, based on 1 mol of compound (1) or a salt thereof.
Examples of the solvent include those used in the reaction for preparing the Grineer reagent.
The reaction is usually carried out at -100 to 60 ° C, preferably -10 to 30 ° C. The reaction time is usually about 5 minutes to about 20 hours, preferably about 30 minutes to about 3 hours.

Process 2
In this step, compound (2) or a salt thereof is subjected to an amidation reaction using ammonia to obtain compound (3) or a salt thereof. The reaction is carried out in a solvent.
Ammonia should be used as an alcohol solution (eg, ethanol solution). The amount of ammonia used is usually 1 to 1000 mol, preferably 1 to 20 mol, relative to 1 mol of compound (2) or a salt thereof.
Examples of the solvent include alcohols, ethers, amides, water and the like.
The reaction is usually carried out at −80 to 120 ° C., preferably 0 to 30 ° C. The reaction time is usually from about 5 minutes to about 100 hours, preferably from about 1 hour to about 48 hours.

Process 3
In this step, compound (3) or a salt thereof is subjected to a vinylization reaction to obtain compound (4) or a salt thereof.
As the vinylization reaction, a Heck reaction using ethylene gas or a cross-coupling reaction using a vinyl trifluoroborate salt can be adopted.

The Heck reaction using ethylene gas is carried out in a solvent in the presence of a palladium catalyst.
The working pressure of ethylene gas is usually 0.1 to 10 MPa, preferably 0.5 to 1.5 MPa.
Regarding the palladium catalyst, examples of the palladium source include palladium (II) chloride, palladium (II) acetate, tetrakistriphenylphosphine palladium (0), tris (dibenzylideneacetone) dipalladium (0), allylpalladium (II) chloride dimer and the like. Can be mentioned. As ligands, bis [2- (diphenylphosphino) phenyl] ether (DPEphos), triphenylphosphine, 1,1'-bis (diphenylphosphino) ferrocene (dppf), 4,5'-bis (diphenyl) Hosphino) -9,9'-dimethylxanthene (xantphos), 1,3-di-tert-butylimidazolium and the like can be mentioned. The amount of the palladium source used is usually 0.0001 to 1 mol, preferably 0.005 to 0.2 mol, based on 1 mol of the compound (3) or a salt thereof. The amount of the ligand used is generally 0.5 to 20 mol, preferably 1 to 10 mol, relative to 1 mol of the palladium source. The palladium catalyst is prepared in the system from a palladium source and a ligand, or is prepared in advance.
The reaction may be carried out in the presence of a polymerization inhibitor. Examples of the polymerization inhibitor include phenothiazine, 2,6-di-tert-butyl-p-cresol (BHT), hydroquinone and the like. The amount of the polymerization inhibitor used is usually 0.001 to 0.2 mol, preferably 0.005 to 0.05 mol, based on 1 mol of the compound (3) or a salt thereof.
The reaction may be carried out in the presence of a base. Examples of the base include organic bases, inorganic bases, metal alkoxides and the like. The amount of the base used is usually 1 to 50 mol, preferably 1 to 10 mol, relative to 1 mol of compound (3) or a salt thereof.
The reaction may be carried out in the presence of additives. Examples of the additive include lithium chloride and the like. The amount of the additive used is usually 0.01 to 1 mol, preferably 0.05 to 0.5 mol, based on 1 mol of the compound (3) or a salt thereof.
Examples of the solvent include amides, alcohols, nitriles, ethers, aromatic hydrocarbons and the like.
The reaction is usually carried out at −20 to 200 ° C., preferably 0 to 120 ° C. The reaction time is usually about 1 to about 48 hours, preferably about 6 to about 24 hours.

The cross-coupling reaction with the vinyl trifluoroborate salt is carried out in a solvent in the presence of a palladium catalyst.
Examples of the vinyl trifluoroborate salt include potassium vinyl trifluoroborate, and the amount of the vinyl trifluoroborate salt used is usually 0.8 to 10 mol, preferably 0.8 to 10 mol, based on 1 mol of the compound (3) or its salt. Is 1-5 mol.
Regarding the palladium catalyst, examples of the palladium source include palladium (II) chloride, palladium (II) acetate, tetrakistriphenylphosphine palladium (0), tris (dibenzylideneacetone) dipalladium (0), allylpalladium (II) chloride dimer and the like. Can be mentioned. As ligands, bis [2- (diphenylphosphino) phenyl] ether (DPEphos), triphenylphosphine, 1,1'-bis (diphenylphosphino) ferrocene (dppf), 4,5'-bis (diphenyl) Hosphino) -9,9'-dimethylxanthene (xantphos), 1,3-di-tert-butylimidazolium and the like can be mentioned. The amount of the palladium source used is usually 0.0001 to 1 mol, preferably 0.001 to 0.2 mol, relative to 1 mol of compound (3) or a salt thereof. The amount of the ligand used is generally 0.5 to 20 mol, preferably 1 to 10 mol, relative to 1 mol of the palladium source. The palladium catalyst is prepared in the system from a palladium source and a ligand, or is prepared in advance.
The reaction may be carried out in the presence of a polymerization inhibitor. Examples of the polymerization inhibitor include phenothiazine, 2,6-di-tert-butyl-p-cresol (BHT), hydroquinone and the like. The amount of the polymerization inhibitor used is usually 0.001 to 0.2 mol, preferably 0.005 to 0.05 mol, based on 1 mol of the compound (3) or a salt thereof.
The reaction may be carried out in the presence of a base. Examples of the base include organic bases, inorganic bases, metal alkoxides and the like. The amount of the base used is usually 1 to 50 mol, preferably 1 to 10 mol, relative to 1 mol of compound (3) or a salt thereof.
Examples of the solvent include alcohols, ethers, nitriles, amides, aromatic hydrocarbons, water and the like.
The reaction is usually carried out at −20 to 200 ° C., preferably 0 to 120 ° C. The reaction time is usually about 1 to about 24 hours, preferably about 1 to about 12 hours.

Step 4
In this step, compound (4) or a salt thereof is subjected to a cyclization reaction using ammonia to obtain compound (5) or a salt thereof. The reaction is carried out in a solvent.
The amount of ammonia used is usually 1 to 1000 mol, preferably 1 to 100 mol, per 1 mol of compound (4) or a salt thereof.
The reaction may be carried out in the presence of a polymerization inhibitor. Examples of the polymerization inhibitor include phenothiazine, 2,6-di-tert-butyl-p-cresol (BHT), hydroquinone and the like. The amount of the polymerization inhibitor used is usually 0.001 to 0.1 mol, preferably 0.005 to 0.05 mol, based on 1 mol of the compound (4) or a salt thereof.
Examples of the solvent include alcohols and water.
The reaction is usually carried out at −80 to 200 ° C., preferably 0 to 100 ° C. The reaction time is usually about 1 to about 24 hours, preferably about 1 to about 12 hours.

Step 5
In this step, compound (5) or a salt thereof is subjected to an asymmetric reduction reaction to obtain compound (6) or a salt thereof. The reaction is carried out by reacting compound (5) or a salt thereof with a hydrogen source in a solvent in the presence of an asymmetric catalyst.
Examples of the hydrogen source include ammonium formate, isopropyl alcohol, formic acid, hydrogen and the like. The amount of the hydrogen source used is usually 1 to 100 mol, preferably 1 to 10 mol, per 1 mol of compound (5) or a salt thereof. When hydrogen gas is used, it is overused under pressure.
As asymmetric catalysts, chloride (p-cymene) [(R, R) -N- (isobutanesulfonyl) -1,2-diphenylethylenediamine] ruthenium (II), chloride [(S) -2,2'-bis (Diphenylphosphino) -1,1'-binaphthyl] [(S, S) -1,2-diphenylethylenediamine] ruthenium (II), chloride [(R) -1-[(S) -2-{bis ( 4-methoxy-3,5-dimethylphenyl) phosphino} ferrosenyl] ethyldi-tert-butyl-phosphine] rhodium (I) and the like can be mentioned. The amount of the asymmetric catalyst used is usually 0.0001 to 1 mol, preferably 0.001 to 0.2 mol, relative to 1 mol of compound (5) or a salt thereof.
Examples of the solvent include nitriles, alcohols, amides, aromatic hydrocarbons, organic bases and the like.
The reaction is usually carried out at −20 to 200 ° C., preferably 0 to 120 ° C. The reaction time is usually about 1 to about 72 hours, preferably about 1 to about 48 hours.
After completion of the reaction, compound (6) or a salt thereof may not be isolated or produced, and may be subjected to the next step 6 as it is as a reaction mixture or after normal post-treatment.

Step 6
In this step, compound (6) or a salt thereof is subjected to a t-butoxycarbonyl (Boc) conversion reaction to obtain compound (7) or a salt thereof. The reaction is carried out by reacting compound (6) or a salt thereof with a Boc agent in a solvent in the presence of a base.
Examples of the Boc agent include di-tert-butyl dicarbonate, t-butoxycarbonyl chloride and the like. The amount of the Boc agent used is usually 1 to 100 mol, preferably 1 to 20 mol, relative to 1 mol of compound (6) or a salt thereof.
Examples of the base include inorganic bases and organic bases. The amount of the base used is usually 1 to 1000 mol, preferably 1 to 100 mol, with respect to 1 mol of the compound (6) or a salt thereof, and organic bases may be used as a solvent.
Examples of the solvent include nitriles, aromatic hydrocarbons, ethers, amides, organic bases, water and the like.
The reaction is usually carried out at −20 to 200 ° C., preferably 0 to 120 ° C. The reaction time is usually about 5 minutes to about 24 hours, preferably about 5 minutes to about 12 hours.

Step 7
In this step, compound (8) is subjected to a halogen exchange reaction to obtain compound (9). The reaction is carried out by reacting compound (8) with an iodide agent in a solvent in the presence of a copper catalyst.
Examples of the iodide agent include sodium iodide, potassium iodide, iodine and the like. The amount of the iodide agent used is usually 1 to 100 mol, preferably 1 to 10 mol, per 1 mol of compound (8).
Regarding the copper catalyst, examples of the copper source include copper (I) iodide, copper (I) chloride, copper (I) oxide, copper (I) thiophen-2-carboxylate and the like. Examples of the ligand include N, N-dimethylethylenediamine (DMEDA), ethylenediamine, ethylene glycol, proline, phenanthroline and the like. The amount of the copper source used is usually 0.001 to 10 mol, preferably 0.01 to 0.2 mol, per 1 mol of compound (8). The amount of the ligand used is usually 1 to 20 mol, preferably 1 to 5 mol, relative to 1 mol of the copper source. The copper catalyst is prepared in the system from a copper source and a ligand, or a pre-prepared one is used.
Examples of the solvent include ethers, nitriles, aromatic hydrocarbons, amides, sulfoxides and the like.
The reaction is usually carried out at −20 to 200 ° C., preferably 0 to 120 ° C. The reaction time is usually about 1 to about 48 hours, preferably about 1 to about 24 hours.

Step 8
In this step, compound (7) or a salt thereof is reacted with compound (9) to obtain compound (10) or a salt thereof. The reaction is carried out in a solvent in the presence of a base and a copper catalyst.
The amount of compound (9) to be used is generally 0.8 to 10 mol, preferably 1 to 2 mol, relative to 1 mol of compound (7) or a salt thereof.
Examples of the base include inorganic bases and organic bases. The amount of the base used is usually 1 to 100 mol, preferably 1 to 10 mol, relative to 1 mol of compound (7) or a salt thereof.
Regarding the copper catalyst, examples of the copper source include copper (I) iodide, copper (I) chloride, copper (I) oxide, copper (I) thiophen-2-carboxylate and the like. Examples of the ligand include N, N-dimethylethylenediamine (DMEDA), ethylenediamine, ethylene glycol, proline, phenanthroline and the like. The amount of the copper source used is usually 0.001 to 10 mol, preferably 0.1 to 2 mol, per 1 mol of compound (7) or a salt thereof. The amount of the ligand used is usually 1 to 20 mol, preferably 1 to 5 mol, relative to 1 mol of the copper source. The copper catalyst is prepared in the system from a copper source and a ligand, or a pre-prepared one is used.
Examples of the solvent include aromatic hydrocarbons, nitriles, ethers, amides, sulfoxides and the like.
The reaction is usually carried out at −20 to 200 ° C., preferably 0 to 120 ° C. The reaction time is usually about 1 to about 72 hours, preferably about 12 to about 48 hours.

Step 9
In this step, compound (10) or a salt thereof is subjected to a deBocification reaction to obtain compound (11) or a salt thereof.
The reaction is carried out by treating with an inorganic acid or an organic acid in a solvent.
Acids are usually overused.
Examples of the solvent include water, alcohols, ethers, esters and the like.
The reaction is usually carried out at −5 to 100 ° C., preferably 0 to 60 ° C. The reaction time is usually about 1 to about 48 hours, preferably about 1 to about 24 hours.

Step 10
In this step, compound (12) or a salt thereof is subjected to a benzyl esterification reaction to obtain compound (13). The reaction is carried out by reacting compound (12) or a salt thereof with benzyl alcohol in a solvent in the presence of a condensing agent.
The amount of benzyl alcohol used is generally 0.8 to 100 mol, preferably 1 to 10 mol, relative to 1 mol of compound (12) or a salt thereof.
Condensing agents include 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCl), O- (7-azabenzotriazole-1-yl) -N, N, N', N'-tetra. Examples thereof include methyluronium hexafluorophosphate (HATU), di-tert-butyl dicarbonate, and carbonyldiimidazole (CDI). The amount of the condensing agent used is usually 1 to 100 mol, preferably 1 to 10 mol, relative to 1 mol of compound (12) or a salt thereof.
The reaction may be carried out in the presence of additives. Examples of the additive include 4-dimethylaminopyridine, 1-hydroxybenzotriazole (HOBt) and the like. The amount of the additive used is usually 0.01 to 10 mol, preferably 0.01 to 2 mol, relative to 1 mol of compound (12) or a salt thereof.
Examples of the solvent include nitriles, esters, ethers, halogenated hydrocarbons, amides and the like.
The reaction is usually carried out at −20 to 200 ° C., preferably 0 to 120 ° C. The reaction time is usually about 1 to about 48 hours, preferably about 1 to about 24 hours.
After completion of the reaction, compound (13) may not be isolated or produced, and may be subjected to the next step 11 as it is as a reaction mixture or after normal post-treatment.

Step 11
In this step, compound (13) is reacted with Meldrum's acid to obtain compound (14). The reaction is carried out in a solvent in the presence of a base.
The amount of meldrum's acid used is usually 1 to 100 mol, preferably 1 to 10 mol, per 1 mol of compound (13).
Examples of the base include organic bases and the like. The amount of the base used is usually 0.001 to 10 mol, preferably 0.01 to 1 mol, based on 1 mol of compound (13).
Examples of the solvent include alcohols, esters, ethers and the like.
The reaction is usually carried out at −20 to 150 ° C., preferably 0 to 120 ° C. The reaction time is usually about 16 to about 72 hours, preferably about 16 to about 48 hours.

Step 12
In this step, compound (14) is subjected to a reduction reaction using a reducing agent to obtain compound (15). The reaction is carried out by reacting compound (14) with a reducing agent in a solvent.
Examples of the reducing agent include sodium borohydride, sodium triacetoxyborohydride, sodium cyanoborohydride and the like. The amount of the reducing agent used is usually 0.2 to 100 mol, preferably 0.2 to 10 mol, per 1 mol of compound (14).
Examples of the solvent include ethers, alcohols, nitriles, amides, aromatic hydrocarbons, esters and the like.
The reaction is usually carried out at −90 to 60 ° C., preferably −50 to 30 ° C. The reaction time is usually about 0.5 to about 24 hours, preferably about 0.5 to about 12 hours.
In the reaction, the reduction proceeds diastereoselectively, and the cis form is preferentially produced (cis / trans = about 10/1 to 11/1 (dr)). Then, by repeating recrystallization, the compound (15) which is a cis form with higher purity can be obtained (cis / trans = about 99.5 / 0.5 (dr)). Ethyl acetate / 2-propanol is preferable as the recrystallization solvent, and recrystallization is carried out in a temperature range of 15 to 35 ° C. for about 2 to 96 hours.

Step 13
In this step, compound (15) is reacted with t-butanol to give compound (16). The reaction is carried out in a solvent in the presence of a base.
The amount of t-butanol used is generally 1 to 100 mol, preferably 1 to 10 mol, per 1 mol of compound (15).
Examples of the base include organic bases and the like. The amount of the base used is usually 1 to 100 mol, preferably 1 to 10 mol, per 1 mol of compound (15).
Examples of the solvent include aromatic hydrocarbons, amides, sulfoxides and the like.
The reaction is usually carried out at 20-200 ° C, preferably 50-150 ° C. The reaction time is usually about 16 to about 72 hours, preferably about 16 to about 48 hours.
After completion of the reaction, compound (16) may not be isolated or produced, and may be subjected to the next step 14 as it is as a reaction mixture or after normal post-treatment.

Step 14
In this step, compound (16) is subjected to a catalytic reduction reaction to obtain compound (17) or a salt thereof. The reaction is carried out by reacting compound (16) in a solvent in the presence of a palladium catalyst in a hydrogen atmosphere.
Examples of the palladium catalyst include palladium-carbon and palladium-aluminum. The amount of the palladium catalyst used is usually 0.001 to 10 mol, preferably 0.01 to 2 mol, per 1 mol of compound (16).
Examples of the solvent include esters, alcohols, ethers, nitriles, aromatic hydrocarbons, ketones, halogenated hydrocarbons and the like.
The reaction is usually carried out at −20 to 150 ° C., preferably 0 to 80 ° C. The reaction time is usually about 16 to about 96 hours, preferably about 16 to about 48 hours.
After completion of the reaction, compound (17) or a salt thereof may not be isolated or produced, and may be subjected to the next step 15 as it is as a reaction mixture or after normal post-treatment.

Step 15
In this step, compound (17) or a salt thereof is subjected to salt formation with (S) -1-phenethylamine to obtain compound (18). The reaction is carried out by mixing compound (17) and (S) -1-phenethylamine in a solvent. When the compound (17) is a salt, it is converted into a free form (compound (17)) with an acid and then mixed with (S) -1-phenethylamine.
The amount of (S) -1-phenethylamine used is generally 0.8 to 100 mol, preferably 1 to 10 mol, per 1 mol of compound (17).
Examples of the acid include inorganic acids and organic acids. The amount of the acid used is usually 1 to 100 equivalents, preferably 1 to 10 equivalents, relative to the salt of compound (17).
Examples of the solvent include esters, alcohols, nitriles, aromatic hydrocarbons, ketones, ethers and the like.
The reaction is usually carried out at −20 to 100 ° C., preferably 0 to 60 ° C.

Step 16
In this step, compound (11) or a salt thereof is reacted with compound (18) to obtain compound (19) or a salt thereof. The reaction is carried out in a solvent in the presence of a condensing agent.
The amount of compound (18) to be used is generally 0.5 to 10 mol, preferably 0.8 to 2 mol, relative to 1 mol of compound (11) or a salt thereof.
Condensing agents include 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCl), O- (7-azabenzotriazole-1-yl) -N, N, N', N'-tetra. Methyluronium hexafluorophosphate (HATU) and the like can be mentioned. The amount of the condensing agent used is usually 1 to 10 mol, preferably 1 to 5 mol, relative to 1 mol of compound (11) or a salt thereof.
The reaction may be carried out in the presence of a base.
Examples of the base include inorganic bases and organic bases. The amount of the base used is usually 1 to 100 mol, preferably 1 to 10 mol, relative to 1 mol of compound (11) or a salt thereof.
Examples of the solvent include nitriles and ethers.
The reaction is usually carried out at −20 to 200 ° C., preferably 0 to 120 ° C. The reaction time is usually about 1 to about 24 hours, preferably about 1 to about 12 hours.

Step 17
In this step, compound (19) or a salt thereof is subjected to an acid hydrolysis reaction to obtain compound (A) or a salt thereof. The reaction is carried out by treating with an inorganic acid or an organic acid in a solvent.
The amount of the acid used is usually 0.1 to 1000 mol, preferably 1 to 100 mol, per 1 mol of the compound (19) or a salt thereof.
Examples of the solvent include nitriles, esters, ethers, water and the like.
The reaction is usually carried out at −20 to 200 ° C., preferably 0 to 120 ° C. The reaction time is usually about 1 to about 72 hours, preferably about 6 to about 48 hours.

In Scheme 1, compound (2), compound (3), compound (4), compound (5), compound (6), compound (7), compound (9), compound (14), compound (15) and compound. (16) is a novel compound.
Further, in Scheme 1, Steps 1 to 8 are new routes for producing compound (10), and Steps 10 to 15 are new routes for producing compound (18).
According to Scheme 1, the total yield of compound (A) or a salt thereof is 13 in 10 steps (excluding sub-steps) without the need for cryogenic reaction conditions or complicated operations such as column purification and chiral column purification. It can be manufactured at ~ 22%.

Compound (A) or a salt thereof can also be produced by the process shown in Scheme 2 below.

(Each group in the formula has the same meaning as above.)

Step 18
In this step, compound (20) or a salt thereof is subjected to a t-butoxycarbonyl (Boc) conversion reaction to obtain compound (21). The reaction is carried out by reacting compound (20) or a salt thereof with a Boc agent in a solvent in the presence of a base.
Examples of the Boc agent include di-tert-butyl dicarbonate, t-butoxycarbonyl chloride and the like. The amount of the Boc agent used is generally 0.8 to 100 mol, preferably 1 to 50 mol, relative to 1 mol of compound (20) or a salt thereof.
Examples of the base include inorganic bases and organic bases. The amount of the base used is generally 0.8 to 100 mol, preferably 1 to 50 mol, relative to 1 mol of compound (20) or a salt thereof.
Examples of the solvent include alcohols, esters, halogenated hydrocarbons and the like.
The reaction is usually carried out at −20 to 100 ° C., preferably 0 to 60 ° C. The reaction time is usually about 1 to about 48 hours, preferably about 1 to about 24 hours.
After completion of the reaction, compound (21) may not be isolated or produced, and may be subjected to the next step 19 as it is as a reaction mixture or after normal post-treatment.

Step 19
In this step, compound (21) is reacted with compound (22) or a salt thereof to obtain compound (23) or a salt thereof. The reaction is carried out by reacting compound (21) with compound (22) or a salt thereof in the presence of manganese powder and a nickel catalyst.
The amount of manganese powder used is usually 1 to 100 mol, preferably 2 to 10 mol, per 1 mol of compound (22) or a salt thereof.
The amount of compound (21) to be used is generally 1 to 100 mol, preferably 1 to 20 mol, relative to 1 mol of compound (22) or a salt thereof.
Regarding the nickel catalyst, examples of the nickel source include nickel (II) bromide trihydrate, nickel (II) bromide, nickel (II) chloride and the like. Examples of the ligand include phenanthroline, bassofenanthroline, 4,4'-ditert-butyl-2,2'-bipyridine and the like. The amount of the nickel source used is generally 0.01 to 10 mol, preferably 0.05 to 1 mol, per 1 mol of compound (22). The amount of the ligand used is usually 1-10 mol, preferably 1-5 mol, per 1 mol of nickel source. The nickel catalyst is prepared in the system from a nickel source and a ligand, or a pre-prepared one is used.
Examples of the solvent include amides, esters, ethers, nitriles and the like.
The reaction is usually carried out at 0 to 200 ° C, preferably 0 to 100 ° C. The reaction time is usually about 15 to about 120 hours, preferably about 15 to about 72 hours.
After completion of the reaction, compound (23) or a salt thereof may not be isolated or produced, and may be subjected to the next step 20 as it is as a reaction mixture or after normal post-treatment.

Process 20
In this step, compound (23) or a salt thereof is subjected to a deBocification reaction to obtain compound (24) or a salt thereof. The reaction is carried out by treating compound (23) or a salt thereof with an acid.
Examples of the acid include organic acids and inorganic acids. The amount of the acid used is generally 0.2 to 50 mol, preferably 1 to 10 mol, relative to compound (23) or a salt thereof.
Examples of the solvent include esters, ethers, water and the like.
The reaction is usually carried out at −20 to 200 ° C., preferably 0 to 120 ° C. The reaction time is usually about 1 to about 24 hours, preferably about 1 to about 12 hours.
After completion of the reaction, compound (24) or a salt thereof may not be isolated or produced, and may be subjected to the next step 21 as it is as a reaction mixture or after normal post-treatment.

Step 21
In this step, compound (24) or a salt thereof is subjected to a cyclization reaction using ethyl glyoxylate to obtain compound (25) or a salt thereof. The reaction is carried out in a solvent in the presence of an acid.
As ethyl glyoxylate, a commercially available product such as a toluene solution in polymer form can be used. The amount of ethyl glyoxylate used is generally 0.8 to 100 mol, preferably 1 to 10 mol, relative to 1 mol of compound (24) or a salt thereof.
Examples of the acid include inorganic acids and organic acids. The amount of the acid used is generally 0.1 to 100 mol, preferably 1 to 10 mol, per 1 mol of compound (24) or a salt thereof.
Examples of the solvent include alcohols, aromatic hydrocarbons, ethers and the like.
The reaction is usually carried out at 0 to 200 ° C, preferably 25 to 120 ° C. The reaction time is usually about 6 to about 96 hours, preferably about 12 to about 48 hours.

Step 22
In this step, compound (25) or a salt thereof is subjected to a t-butoxycarbonyl (Boc) conversion reaction to obtain compound (26) or a salt thereof. The reaction is carried out by reacting compound (25) or a salt thereof with a Boc agent in a solvent in the presence of a base.
Examples of the Boc agent include di-tert-butyl dicarbonate, t-butoxycarbonyl chloride and the like. The amount of the Boc agent used is usually 0.8 to 3 mol, preferably 1 to 1.5 mol, relative to 1 mol of compound (25) or a salt thereof.
Examples of the base include inorganic bases and organic bases. The amount of the base used is usually 0.8 to 3 mol, preferably 1 to 1.5 mol, relative to 1 mol of compound (25) or a salt thereof.
Examples of the solvent include alcohols, ethers, aromatic hydrocarbons, saturated hydrocarbons, amides, halogenated hydrocarbons, nitriles, sulfoxides, esters, ketones and the like.
The reaction is usually carried out at 10 to 80 ° C, preferably 30 to 60 ° C. The reaction time is usually about 30 minutes to about 5 hours, preferably about 1 to about 2 hours.

Process 23
In this step, compound (26) or a salt thereof is subjected to a methylation reaction to obtain compound (27) or a salt thereof. The reaction is carried out by reacting compound (26) or a salt thereof with a methylating agent in a solvent.
Examples of the methylating agent include methyl iodide, trimethyloxonium tetrafluoroborate and the like. The amount of the methylating agent used is generally 1-10 mol, preferably 3-7 mol, per 1 mol of compound (26) or a salt thereof.
When methyl iodide is used, the reaction is carried out in the presence of a base. Examples of the base include silver (I) carbonate, potassium carbonate, sodium carbonate, triethylamine, isopropylethylamine and the like. The amount of the base used is usually 0.3 to 5 mol, preferably 0.4 to 1 mol, relative to 1 mol of compound (26) or a salt thereof.
Examples of the solvent include ethers, alcohols, aromatic hydrocarbons, saturated hydrocarbons, amides, halogenated hydrocarbons, esters, ketones, nitriles and the like.
The reaction is usually carried out at 0 to 50 ° C, preferably 15 to 35 ° C. The reaction time is usually about 6 to about 96 hours, preferably about 12 to about 48 hours.
After completion of the reaction, compound (27) or a salt thereof may not be isolated or produced, and may be subjected to the next step 24 as it is as a reaction mixture or after normal post-treatment.

Process 24
In this step, compound (27) or a salt thereof is subjected to an alkali hydrolysis reaction to obtain compound (28) or a salt thereof. The reaction is carried out by treating compound (27) or a salt thereof with an alkali in a solvent.
Examples of the alkali include an aqueous solution of lithium hydroxide, an aqueous solution of sodium hydroxide, an aqueous solution of potassium hydroxide and the like. The amount of alkali used is usually 0.5 to 5 equivalents, preferably 1 to 3 equivalents, relative to compound (27) or a salt thereof.
Examples of the solvent include alcohols, ethers, amides, water and the like.
The reaction is usually carried out at 5-50 ° C, preferably 15-35 ° C. The reaction time is usually about 30 minutes to about 10 hours, preferably about 1 to about 5 hours.
After completion of the reaction, compound (28) or a salt thereof may not be isolated or produced, and may be subjected to the next step 25 as it is as a reaction mixture or after normal post-treatment.

Process 25
In this step, compound (28) or a salt thereof is subjected to optical resolution utilizing diastereomeric salt formation with (1S, 2R) -2-amino-1,2-diphenylethanol to obtain compound (29). obtain.
The optical resolution is carried out by mixing compound (28) with (1S, 2R) -2-amino-1,2-diphenylethanol in a solvent and collecting the precipitated crystals by filtration. When compound (28) is a salt, it is converted to a free form (compound (28)) using an acid or base, and then mixed with (1S, 2R) -2-amino-1,2-diphenylethanol. It is done by.
The amount of (1S, 2R) -2-amino-1,2-diphenylethanol used is usually 0.3 to 2 mol, preferably 0.4 to 1 mol, based on 1 mol of compound (28) or a salt thereof. Is.
Examples of the acid include inorganic acids and organic acids. The amount of the acid used is usually 0.5 to 5 equivalents, preferably 1 to 3 equivalents, relative to the salt of compound (28).
Examples of the base include inorganic bases and organic bases. The amount of the base used is usually 0.5 to 5 equivalents, preferably 1 to 3 equivalents, relative to the salt of compound (28).
Solvents for mixing with (1S, 2R) -2-amino-1,2-diphenylethanol include nitriles, alcohols, ethers, aromatic hydrocarbons, saturated hydrocarbons, amides, and halogenations. Hydrocarbons and the like can be mentioned.
Mixing is usually carried out at 0-100 ° C, preferably 10-70 ° C. The reaction time is usually about 1 to about 48 hours, preferably about 5 to about 24 hours.

Step 26
In this step, compound (30) or a salt thereof is converted to acid chloride and then subjected to a Friedel-Crafts reaction to obtain compound (31).
Conversion of compound (30) or a salt thereof to acid chloride is carried out by reacting compound (30) or a salt thereof with a chlorinating agent in a solvent.
Examples of the chlorinating agent include thionyl chloride, oxalyl chloride, phosphorus oxychloride and the like. The amount of the chlorinating agent used is usually 0.5 to 5 mol, preferably 1 to 3 mol, based on 1 mol of the compound (30) or a salt thereof.
If desired, a catalytic amount of N, N-dimethylformamide may be added to the reaction.
Examples of the solvent include halogenated hydrocarbons, aromatic hydrocarbons, saturated hydrocarbons, amides and the like.
The reaction is usually carried out at 0 to 50 ° C, preferably 10 to 35 ° C. The reaction time is usually about 1 to about 8 hours, preferably about 1 to about 4 hours.
After conversion to acid chloride, the Friedel-Crafts reaction is followed. The Friedel-Crafts reaction is carried out in a solvent in the presence of Lewis acid.
Examples of Lewis acid include aluminum chloride, iron chloride, tin chloride and the like. The amount of Lewis acid used is usually 0.5-5 mol, preferably 1-3 mol, relative to 1 mol of compound (30) or a salt thereof.
Examples of the solvent include those used in the conversion to acid chloride.
The reaction is usually carried out at 0 to 50 ° C, preferably 10 to 35 ° C. The reaction time is usually about 1 to about 56 hours, preferably about 6 to about 28 hours.

Process 27
In this step, compound (31) is reacted with benzylamine to give compound (32) or a salt thereof. The reaction is carried out in a solvent in the presence of a palladium catalyst and a base.
Examples of the palladium catalyst include tris (dibenzylideneacetone) dipalladium [Pd ₂ (dba) ₃ ], palladium acetate, tetrakisphinephosphine palladium and the like. The amount of the palladium catalyst used is usually 0.01 to 0.5 mol, preferably 0.02 to 0.1 mol, based on 1 mol of compound (31).
Examples of the base include metal alkoxides, inorganic bases, organic bases and the like. The amount of the base used is usually 0.5 to 3 mol, preferably 1 to 2 mol, based on 1 mol of compound (31).
If necessary, ligands such as 2,2'-bis (diphenylphosphine) -1,1'-binaphthyl (BINAP) and triphenylphosphine may be added to the reaction. The amount of the ligand used is usually 0.01 to 0.5 mol, preferably 0.02 to 0.1 mol, relative to 1 mol of compound (31).
Examples of the solvent include aromatic hydrocarbons, ethers, nitriles, alcohols, saturated hydrocarbons, amides, halogenated hydrocarbons, esters, ketones and the like.
The reaction is usually carried out at 20 to 120 ° C, preferably 60 to 100 ° C. The reaction time is usually about 1 to about 12 hours, preferably about 1 to about 6 hours.
After completion of the reaction, compound (32) or a salt thereof may not be isolated or produced, and may be subjected to the next step 28 as it is as a reaction mixture or after normal post-treatment.

Step 28
In this step, compound (32) or a salt thereof is subjected to a reduction reaction using a reducing agent to obtain compound (33) or a salt thereof. The reaction is carried out by reacting compound (32) or a salt thereof with a reducing agent in a solvent.
Examples of the reducing agent include sodium borohydride, lithium aluminum hydride, diisobutylaluminum hydride, sodium bis (2-methoxyethoxy) aluminum hydride and the like. The amount of the reducing agent used is usually 0.3 to 3 mol, preferably 0.7 to 1.5 mol, based on 1 mol of compound (32) or a salt thereof.
Examples of the solvent include alcohols, ethers, aromatic hydrocarbons, saturated hydrocarbons and the like.
The reaction is usually carried out at −20 to 70 ° C., preferably 0 to 30 ° C. The reaction time is usually about 5 minutes to about 12 hours, preferably about 1 to about 6 hours.

Process 29
In this step, compound (33) or a salt thereof is subjected to a catalytic reduction reaction to obtain compound (34) or a salt thereof. The reaction is carried out by reacting compound (33) or a salt thereof in a solvent in the presence of a palladium catalyst in a hydrogen atmosphere.
Examples of the palladium catalyst include palladium-carbon and palladium-alumina. The amount of the palladium catalyst used is usually 0.001 to 0.5 mol, preferably 0.01 to 0.02 mol, based on 1 mol of the compound (33) or a salt thereof.
Examples of the solvent include alcohols, ethers, aromatic hydrocarbons, saturated hydrocarbons, amides, halogenated hydrocarbons, esters, ketones and the like.
The reaction is usually carried out at 0 to 100 ° C, preferably 30 to 85 ° C. The reaction time is usually about 12 to about 192 hours, preferably about 24 to about 96 hours.
After completion of the reaction, compound (34) or a salt thereof may not be isolated or produced, and may be subjected to the next step 30 as it is as a reaction mixture or after normal post-treatment.

Process 30
In this step, compound (34) or a salt thereof is subjected to salt formation with (+)-camphorsulfonic acid to give compound (35). The reaction is carried out by mixing compound (34) and (+)-camphorsulfonic acid in a solvent. When compound (34) is a salt, it is converted into a free form (compound (34)) using a base and then mixed with (+)-camphorsulfonic acid.
The amount of (+)-camphorsulfonic acid used is generally 0.5 to 3 mol, preferably 0.7 to 1.5 mol, per 1 mol of compound (34).
Examples of the base include inorganic bases and organic bases. The amount of the base used is usually 0.5 to 10 equivalents, preferably 1 to 3 equivalents, relative to the salt of compound (34).
Examples of the solvent include esters, nitriles, alcohols, aromatic hydrocarbons, saturated hydrocarbons, amides, halogenated hydrocarbons, sulfoxides, ketones and the like.
The reaction is usually carried out at 0 to 50 ° C, preferably 10 to 40 ° C. The reaction time is usually about 5 minutes to about 5 hours, preferably about 5 minutes to about 2 hours.

Step 31
In this step, compound (29) is reacted with compound (35) to give compound (10) or a salt thereof. The reaction is carried out in a solvent in the presence of a condensing agent.
Condensing agents include 4- (4,6-dimethoxy-1,3,5-triazine-2-yl) -4-methylmorpholinium chloride (DMT-MM), propanephosphonic anhydride (T3P), 1 -(3-Dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCl) and the like can be mentioned. The amount of the condensing agent used is usually 0.5 to 10 mol, preferably 0.8 to 5 mol, per 1 mol of compound (29).
Examples of the solvent include ethers, nitriles, aromatic hydrocarbons, saturated hydrocarbons, amides, halogenated hydrocarbons, sulfoxides, esters, ketones and the like.
The reaction is usually carried out at 0 to 50 ° C, preferably 5 to 40 ° C. The reaction time is usually about 1 to about 20 hours, preferably about 1 to about 10 hours.

Step 32
In this step, compound (10) or a salt thereof is subjected to a deBocification reaction to obtain compound (11) or a salt thereof. The step is performed in the same manner as step 9 of Scheme 1.

Process 33
In this step, compound (36) or a salt thereof is subjected to a catalytic reduction reaction to obtain compound (37) or a salt thereof. The reaction is carried out by reacting compound (36) or a salt thereof in a solvent in the presence of a palladium catalyst in a hydrogen atmosphere.
Examples of the palladium catalyst include palladium-carbon and palladium-alumina. The amount of the palladium catalyst used is usually 0.001 to 0.5 mol, preferably 0.002 to 0.1 mol, based on 1 mol of compound (36) or a salt thereof.
Examples of the solvent include alcohols, ethers, nitriles, aromatic hydrocarbons, saturated hydrocarbons, amides, halogenated hydrocarbons, esters, ketones and the like.
The reaction is usually carried out at 0 to 50 ° C, preferably 10 to 50 ° C. The reaction time is usually about 1 to about 60 hours, preferably about 6 to about 30 hours.
After completion of the reaction, compound (37) or a salt thereof may not be isolated or produced, and may be subjected to the next step 34 as it is as a reaction mixture or after normal post-treatment.

Process 34
In this step, compound (37) or a salt thereof is subjected to salt formation with (S) -1-phenethylamine, and then fractional crystallization is performed to obtain compound (18).
Salt formation with (S) -1-phenethylamine is carried out by mixing compound (37) and (S) -1-phenethylamine in a solvent. When the compound (37) is a salt, it is converted into a free form (compound (37)) with an acid and then mixed with (S) -1-phenethylamine.
The amount of (S) -1-phenethylamine used is usually 0.4 to 2 mol, preferably 0.8 to 1.2 mol, based on 1 mol of compound (37).
Examples of the acid include inorganic acids and organic acids. The amount of the acid used is usually 0.5 to 5 equivalents, preferably 1.5 to 3 equivalents, relative to the salt of compound (37).
Examples of the solvent include esters, ethers, nitriles, alcohols, aromatic hydrocarbons, saturated hydrocarbons, amides, halogenated hydrocarbons, sulfoxides, ketones and the like.
The reaction is usually carried out at 0 to 100 ° C, preferably 5 to 70 ° C. The reaction time is usually about 1 to about 12 hours, preferably about 1 to about 6 hours.
Subsequently, the obtained salt is attached to fractional crystallization.
Examples of the solvent for fractionated crystals include esters, ethers, nitriles, alcohols, aromatic hydrocarbons, saturated hydrocarbons, amides, halogenated hydrocarbons, sulfoxides, ketones and the like. ..
Fractional crystallization is usually carried out at 0 to 100 ° C, preferably 5 to 70 ° C. The reaction time is usually about 1 to about 16 hours, preferably about 1 to about 8 hours.

Process 35
In this step, compound (11) or a salt thereof is reacted with compound (18) to obtain compound (19) or a salt thereof. The step is performed in the same manner as step 16 of Scheme 1.

Step 36
In this step, compound (19) or a salt thereof is subjected to an acid hydrolysis reaction to obtain compound (A) or a salt thereof. The step is performed in the same manner as step 17 of Scheme 1.

In Scheme 2, compound (32) and compound (33) are novel compounds.
Further, in Scheme 2, steps 18 to 20, steps 25, and steps 26 to 31 are new routes for producing compound (10), and steps 33 and 34 are new routes for producing compound (18). ..
According to Scheme 2, the total yield of compound (A) or a salt thereof is 4 in 12 steps (excluding sub-steps) without the need for cryogenic reaction conditions or complicated operations such as column purification and chiral column purification. It can be manufactured at ~ 6%.

The present invention will be further described in detail with reference to the following examples, but these are not limited to the present invention and may be changed without departing from the scope of the present invention.
"Room temperature" in the following examples usually indicates about 10 ° C to about 35 ° C. The ratio shown in the mixed solvent indicates the volume ratio unless otherwise specified. % Indicates% by weight unless otherwise specified.

Unless otherwise specified, the elution in the column chromatography of the example was carried out under observation by TLC (Thin Layer Chromatography, thin layer chromatography). In the TLC observation, 60 F ₂₅₄ manufactured by Merck & Co., Inc. was used as the TLC plate, and the solvent used as the elution solvent in the column chromatography was used as the developing solvent. In addition, a UV detector was used for detection. In silica gel column chromatography, aminopropylsilane-bonded silica gel was used when it was described as NH, and 3- (2,3-dihydroxypropoxy) propylsilane-bonded silica gel was used when it was described as Diol. In preparative HPLC (high performance liquid chromatography), when described as C18, octadecyl-bonded silica gel was used. The ratio shown in the elution solvent indicates the volume ratio unless otherwise specified.
^{1 1} H NMR was measured by Fourier transform type NMR. ^{1 1} H NMR analysis used ACD / SpecManager (trade name) software or the like. Peaks with very gentle proton peaks such as hydroxyl groups and amino groups may not be described.
MS was measured by LC / MS. As the ionization method, the ESI method or the APCI method was used. The data show the measured values (found). Usually, a molecular ion peak is observed, but it may be observed as a fragment ion. In the case of salts, free molecular ion peaks or fragment ion peaks are usually observed.

The unit of sample concentration (c) in optical rotation ([α] _D ) is g / 100 mL.
The elemental analysis value (Anal.) Is shown as a calculated value (Calcd) and an actually measured value (Found).
In the examples, the cis / trans notation included in the compound name basically means a mixture of two optical isomers in a cis or trans configuration when the corresponding partial structure has two asymmetric centers. However, exceptionally, when it is described as optical activity, it represents a single optical isomer.
The peak by powder X-ray diffraction of the example means a peak measured at room temperature using Cu Kα ray as a radiation source and Ultima IV (Rigaku Corporation, Japan). The measurement conditions are as follows.
Electric pressure / Electric current: 40 kV / 50 mA
Scan speed: 6 degree / min
Scan range of 2 Theta: 2-35 degree
The crystallinity of the examples by powder X-ray diffraction was calculated by the Hermans method.

The following abbreviations are used in the following examples.
mp: melting point
MS: Mass spectrum
M: Molarity
N: Normality
CDCl ₃ : Deuterated chloroform
DMSO-d ₆ : Deuterated dimethyl sulfoxide
¹ H NMR: Proton nuclear magnetic resonance
LC / MS: Liquid chromatograph mass spectrometer
ESI: electrospray ionization, electrospray ionization
APCI: atomospheric pressure chemical ionization, atmospheric pressure chemical ionization
DMF: N, N-dimethylformamide
THF: tetrahydrofuran
CH ₃ CN: Acetonitrile
MeOH: Methanol
EtOH: Ethanol
BnOH: Benzyl alcohol
tBuOH: tert-butanol
EtOAc: Ethyl acetate
iPrOAc: Isopropyl acetate
Et ₃ N: Triethylamine
tBu: tert-butyl
Boc: tert-butoxycarbonyl
ⁱ PrMgCl: Isobropill Magnesium Chloride
Pd (dppf) Cl ₂ : [1,1'-bis (diphenylphosphino) ferrocene] dichloropalladium (II)
BHT: 2,6-di-tert-butyl-p-cresol
ⁱ Pr ₂ EtN: Diisopropylethylamine
DPEphos: Bis [2- (diphenylphosphino) phenyl] ether
DMEDA: N, N'-dimethylethylenediamine
DMAP: 4-Dimethylaminopyridine
EDCl: 1- (3-Dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride
CSA: (+)-camphorsulfonic acid
PhSO ₃ H: Benzene sulfonic acid
Pd ₂ (dba) ₃ : Tris (dibenzylideneacetone) dipallad (0)
BINAP: 2,2'-bis (diphenylphosphino) -1,1'-binaphthyl
(Boc) ₂ O: Di-tert-butyl dicarbonate

[Example of Scheme 1]
Synthesis example 1
Synthesis of Ethyl 2- (2-Chloro-6-Methoxypyridin-3-yl) -2-oxoacetate (Compound (2)) (Step 1)

3-Bromo-2-chloro-6-methoxypyridine (120.0 g, 539.4 mmol) and tetrahydrofuran (240 mL) were added to a 1 L four-necked flask. After cooling to 12 ° C., a tetrahydrofuran solution (2M, 269.7 mL) of isobropyrmagnesium chloride was added dropwise, and the mixture was stirred at room temperature for 2 hours. This reaction solution was added dropwise to tetrahydrofuran (240 mL) of diethyl oxalate (87.6 mL) prepared separately while maintaining 1 ° C. or lower. After stirring at 3 ° C. or lower for 1 hour, hydrochloric acid (1M, 600 mL) was added, and the organic layer was separated and extracted. The solvent was replaced with ethanol (480 mL), seed crystals were added, the mixture was stirred at room temperature for 20 minutes, and then water (480 mL) was added dropwise. The suspension was filtered, and the obtained crystals were washed with a 1: 2 mixture of ethanol and water (450 mL) and dried under reduced pressure at 40 ° C. to give the title compound. White to lilac crystalline powder 107.8g, yield 82%.
¹ H NMR (500 MHz, CDCl ₃ ) δ (ppm) 8.07 (d, J = 8.5 Hz, 1H), 6.80 (d, J = 8.5 Hz, 1H), 4.43 (q, J = 7.1 Hz, 2H), 1.42 (t, J = 7.1 Hz, 3H)

Synthesis example 2
Synthesis of 2- (2-chloro-6-methoxypyridin-3-yl) -2-oxoacetamide (compound (3)) (step 2)

Ethyl 2- (2-chloro-6-methoxypyridin-3-yl) -2-oxoacetate (100.0 g, 385.8 mmol) and an ethanol solution of ammonia (2M, 600 mL) were added to a 1 L four-necked flask. After stirring at room temperature for 24 hours, the suspension was filtered and the resulting crystals were washed with ethanol (200 mL). The title compound was obtained by drying under reduced pressure at 40 ° C. White crystalline powder 77.6g, yield 94%.
^{1 1 1} H NMR (500 MHz, CDCl ₃ ) δ (ppm) 8.37 (bs, 1H), 8.13 (d, J = 8.5 Hz, 1H), 8.02 (bs, 1H), 7.00 (d, J = 8.5 Hz, 1H) ), 3.96 (s, 3H)

Synthesis example 3
Synthesis of 2- (6-methoxy-2-vinylpyridine-3-yl) -2-oxoacetamide (compound (4)) (step 3)

2- (2-Chloro-6-methoxypyridine-3-yl) -2-oxoacetamide (30.0 g, 139.8 mmol), potassium vinyl trifluoroborate (22.5 g), [1,1'in a 1 L four-mouth flask -Bis (diphenylphosphino) ferrocene] Dichloropalladium (II) (Pd (dppf) Cl ₂ ) (0.7 g), 2,6-di-tert-butyl-p-cresol (BHT) (0.9 g), N, N-diisopropylethylamine (60.9 mL) and 1-propanol (150 mL) were added, degassed, and then stirred at 95 ° C. for 3.5 hours. The mixture was cooled to 55 ° C., THF (300 mL) was added, and the mixture was stirred for 15 minutes to remove insoluble matter. The resulting solution was concentrated to 169 g and then the solvent was replaced with ethanol (150 mL). The mixture was cooled to 5 ° C., stirred for 1 hour, the suspension obtained was filtered and the crystals were washed with cold ethanol (60 mL). The title compound was obtained by drying under reduced pressure at 45 ° C. Light yellow crystalline powder 22.3g, yield 77%.
^{1 1 1} H NMR (500 MHz, DMSO-d ₆ ) δ (ppm) 8.32 (brs, 1H), 8.03 (d, J = 8.7 Hz, 1H), 7.99 (bs, 1H), 7.39 (dd, J = 10.6, 16.7 Hz, 1H), 6.87 (d, J = 8.7 Hz, 1H), 6.53 (dd, J = 2.2, 16.7 Hz, 1H), 5.65 (dd, J = 2.2, 10.6 Hz, 1H), 3.99 (s, 3H)

Synthesis example 4
Synthesis of 2- (6-methoxy-2-vinylpyridine-3-yl) -2-oxoacetamide (compound (4)) (step 3)

2- (2-Chloro-6-methoxypyridin-3-yl) -2-oxoacetamide (200.0 mg, 0.93 mmol), palladium chloride (8.3 mg), bis [2- (diphenylphosphino) phenyl] in 120 mL autoclave Ether (DPEphos) (25.0 mg), lithium chloride (3.9 mg), tetrahydrofuran (2.0 mL), dimethylformamide (1.0 mL) and triethylamine (390.0 μL) were added. The gas phase was replaced with ethylene gas, and the mixture was stirred at 1.0 MPa at 80 ° C. for 40 hours under an ethylene atmosphere. After cooling the reaction solution to room temperature, the insoluble material was removed by filtration. The obtained solution was concentrated under reduced pressure, THF (20 mL) was added, and the insoluble material was removed by filtration while heating at about 60 ° C. The solvent was replaced with toluene (10 mL) and the resulting precipitate was collected by filtration. The crystals were washed with toluene (5 mL) and dried under reduced pressure to give the title compound. Light yellow crystalline powder 156.2 mg, yield 81%.

Synthesis example 5
Synthesis of 2-methoxy-7,8-dihydro-1,6-naphthalidine-5-carboxyamide (Compound (5)) (Step 4)

2- (6-Methoxy-2-vinylpyridine-3-yl) -2-oxoacetamide (2.0 g, 9.7 mmol), 2,6-di-tert-butyl-p-cresol (BHT) (80 mg) in a 120 mL autoclave ) And methanol (80 mL) were added, and the mixture was stirred at 0.30 MPa at room temperature for 2 hours under an ammonia atmosphere, and then further stirred at 60 ° C. for 6 hours. After cooling the reactor to room temperature, the solvent was replaced with 2-propanol (20 mL) and the resulting precipitate was collected by filtration. The crystals were washed with 2-propanol (8 mL) and dried under reduced pressure at room temperature to give the title compound. White crystalline powder 1.2g, yield 60%.
^{1 1} H NMR (500 MHz, DMSO-d ₆ ) δ (ppm) 8.20 (d, J = 8.7 Hz, 1H), 7.85 (bs, 1H), 7.51 (bs, 1H), 6.75 (d, J = 8.7 Hz) , 1H), 3.91 (s, 3H), 3.83 (t, J = 7.9 Hz, 2H), 2.77 (t, J = 7.9 Hz, 2H)

Synthesis example 6
Synthesis of (R) -tert-butyl 5-carbamoyl-2-methoxy-7,8-dihydro-1,6-naphthalidine-6 (5H) -carboxylate (compound (7)) (steps 5 and 6)

2-Methoxy-7,8-dihydro-1,6-naphthalidine-5-carboxyamide (2.0 g, 9.8 mmol), ammonium formate (1.8 g), chloride as an asymmetric catalyst (p-) in a 100 mL four-necked flask Simene) [(R, R) -N- (isobutanesulfonyl) -1,2-diphenylethylenediamine] ruthenium (II) (58.7 mg) and acetonitrile (50 mL) were added, and the mixture was stirred at 35 ° C. for 24 hours under a nitrogen stream. The aqueous layer was separated by adding aqueous citric acid solution (1M, 24 mL) and toluene (12 mL), and the organic layer was washed twice with aqueous citric acid solution (1M, 12 mL). The obtained aqueous layer was also washed with toluene (12 mL) to obtain a toluene solution of (R) -2-methoxy-5,6,7,8-tetrahydro-1,6-naphthalidine-5-carboxyamide. ..
^{1 1} H NMR (500 MHz, DMSO-d ₆ ) δ (ppm) 7.59 (d, J = 8.5 Hz, 1H), 7.52 (bs, 1H), 7.19 (bs, 1H), 6.60 (d, J = 8.5 Hz) , 1H), 4.29 (s, 1H), 3.79 (s, 3H), 3.03-3.12 (m, 1H), 2.83-2.97 (m, 2H), 2.58-2.75 (m, 2H)
Toluene solution of potassium carbonate (14.5 g) and (Boc) ₂ O (2 mL) was added to this solution, and after stirring at room temperature for 1 hour, the organic layer was separated and the aqueous layer was divided twice with toluene (12 mL). Extracted. The combined organic layer was washed with water (6 mL), the solvent was replaced with methanol (10 mL), and water (10 mL) was added. The precipitate was collected by filtration and washed with a mixture of water (2.7 mL) and methanol (1.3 mL). The title compound was obtained by drying under reduced pressure at 50 ° C. 2.16 g of white crystalline powder, 72% yield, 98.3% ee optical yield.
¹ H NMR (500 MHz, DMSO-d ₆ ) δ (ppm) 7.74-7.84 (m, 1H), 7.71 (bs, 1H), 7.15 (br d, 1H), 6.70 (d, J = 8.51 Hz, 1H ), 5.29 (s, 0.5H), 5.17 (s, 0.5H), 3.82 (s, 3H), 3.73 --3.81 (m, 2H), 2.84 --2.95 (m, 1H), 2.71 --2.82 (m, 1H) ), 1.43 (br d, 9H)

Synthesis example 7
Synthesis of 5-iodo-7-fluoro-1,1-dimethyl-2,3-dihydro-1H-indene (compound (9)) (step 7)

In a 30 mL Schlenk tube, 5-bromo-7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden (2.4 g, 10.0 mmol), copper iodide (95.2 mg), sodium iodide (3.0 g) ), 1,4-Dioxane (10.0 mL) and N, N'-dimethylethylenediamine (DMEDA) (107.5 μL) were added, and the mixture was stirred overnight under heating under reflux. The reaction mixture was cooled to room temperature, filtered through Celite® and the filtrate was washed with ethyl acetate (20 mL). The resulting solution was washed twice with aqueous ammonia (10%, 10 mL), followed by aqueous citric acid (20%, 10 mL) and water (10 mL). The organic layer was concentrated under reduced pressure to give the title compound. Yellow oil 2.7g, yield 94%
¹ H NMR (500 MHz, CDCl ₃ ) δ (ppm) 7.29 (s, 1H), 7.16 (d, J = 9.1 Hz, 1H), 2.89 (t, J = 7.3 Hz, 2H), 1.91 (t, J) = 7.4 Hz, 2H), 1.34 (s, 6H)

Synthesis example 8
(R) -tert-Butyl 5-((7-fluoro-1,1-dimethyl-2,3-dihydro-1H-indene-5-yl) carbamoyl) -2-methoxy-7,8-dihydro-1, Synthesis of 6-naphthylidine-6 (5H) -carboxylate (Compound (10)) (Step 8)

In a 30 mL Schlenck tube, (R) -tert-butyl 5-carbamoyl-2-methoxy-7,8-dihydro-1,6-naphthalene-6 (5H) -carboxylate (2.0 g, 6.5 mmol), potassium carbonate (2.0) g), copper iodide (1.4 g), 5-iodo-7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden (2.2 g), toluene (8.0 mL) and N, N'- Dimethylethylenediamine (DMEDA) (1.6 mL) was added, degassed, and then stirred at room temperature for 30 hours. Ammonia water (25%, 50 mL) and ethyl acetate (16 mL) are added to separate and extract the organic layer, and the organic layer is repeatedly washed with saturated aqueous ammonium chloride solution (16 mL) until the blue color disappears, and then with water (16 mL). Washed. The solvent was replaced with ethanol (2 mL), acetic acid (2 mL) and water (2 mL) were added, then water (9 mL) was further added, and the obtained precipitate was collected by filtration, washed with water (10 mL), and 50. The title compound was obtained by drying under reduced pressure at ° C. White crystalline solid 1.4 g, yield 91%.
^{1 1} H NMR (500 MHz, CDCl ₃ ) δ (ppm) 8.96 (bs, 1H), 7.52 (m, 1H), 7.08 (d, J = 11.6 Hz, 1H), 7.04 (s, 1H), 6.62 (d , J = 8.5Hz, 1H), 5.62 (bs, 1H), 3.95 ―― 4.10 (m, 1H), 3.91 (s, 3H), 3.55 (bs, 1H), 2.87 ―― 2.99 (m, 2H), 2.85 ( t, J = 7.3 Hz, 2H), 1.89 (t, J = 7.4 Hz, 2H), 1.53 (s, 9H), 1.33 (s, 6H)

Synthesis example 9
(5R) -N- (7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl) -5,6,7,8-tetrahydro-2-methoxy-1,6- Synthesis of naphthylidine-5-carboxamide 2benzene sulfonate (2benzene sulfonate of compound (11)) (step 9)

Hydrochloric acid (4M, 102.5 kg) was added to the reactor, and at room temperature (R) -tert-butyl 5-((7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl). ) Carbamoyl) -2-methoxy-7,8-dihydro-1,6-naphthylidine-6 (5H) -carboxylate (32.18 kg) was added in 10 portions. After stirring at room temperature for 12 hours, the reaction solution was added dropwise to a mixed solution of a 20% aqueous potassium carbonate solution (188.3 kg) and ethyl acetate (130.6 kg). After stirring at room temperature for 30 minutes, the liquid was separated to obtain an organic layer. The organic layer was washed with 15% saline (71.6 kg), azeotropically dehydrated while adding ethyl acetate (116.1 kg), the liquid volume was adjusted to 103 L, and the insoluble material was removed by filtration. Acetonitrile (40.5 kg) and water (3.7 kg) were added to the obtained solution, and an ethyl acetate solution of benzenesulfonic acid monohydrate (24.2 kg) was added dropwise at 40 ° C. over 1 hour. After adding seed crystals and stirring for another 1 hour, ethyl acetate (139.3 kg) was added dropwise, and the mixture was stirred at 40 ° C. for 2 hours and then at room temperature for another 6 hours. The crystals were filtered, washed with ethyl acetate (92.9 kg), and dried under reduced pressure at 40 ° C. to give the title compound. White crystalline solid 41.74 kg, yield 89%
¹ H NMR (500 MHz, DMSO-d ₆ ) δ (ppm) 1.31 (d, J = 2.5 Hz, 6H), 1.89 (t, J = 7.4 Hz, 2H), 2.89 (t, J = 7.4 Hz, 2H) ), 2.97 (dt, J = 18.0, 5.5 Hz, 1H), 3.11-3.17 (m, 1H), 3.50-3.60 (m, 1H), 3.78-3.87 (m, 1H), 3.84 (s, 3H), 5.23 (brs, 1H), 5.94 (brs, 2H), 6.77 (d, J = 8.8 Hz, 1H), 7.23 (brs, 1H), 7.29-7.33 (m, 7H), 7.59-7.63 (m, 4H) , 7.69 (d, J = 8.8 Hz, 1H), 9.50 (brs, 1H), 9.76 (brs, 1H), 11.10 (s, 1H).

Synthesis example 10
Synthesis of benzyl3-oxocyclobutanecarboxylate (Compound (13)) (Step 10)

At room temperature, 3-oxocyclobutanecarboxylic acid (100 g, 876 mmol), benzyl alcohol (90.7 mL, 876 mmol) and 4-dimethylaminopyridine (DMAP) (5.35 g, 43.8 mmol) were added to acetonitrile (500 mL). .. 1- (3-Dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCl) (185 g, 964 mmol) was added in portions at 5 ° C. and washed with acetonitrile (100 mL). After stirring at room temperature for about 1 hour, 1 M hydrochloric acid (400 mL) and ethyl acetate (800 mL) were added to separate the liquids. The organic layer was washed successively with 5% aqueous sodium hydrogen carbonate (400 mL) and 10% brine (400 mL), and then concentrated under reduced pressure to about 500 mL. Ethyl acetate (400 mL) was added and concentrated to about 500 mL under reduced pressure twice, and methanol (500 mL) was added and concentrated to about 500 mL under reduced pressure twice. , A methanol solution of the title compound was obtained.
^{1 1} H NMR (500 MHz, CDCl ₃ ) δ (ppm) 3.20-3.31 (m, 3H), 3.34-3.46 (m, 2H), 5.17 (s, 2H), 7.28-7.40 (m, 5H).

Synthesis example 11
Synthesis of benzyl 3- (2,2-dimethyl-4,6-dioxo-1,3-dioxane-5-idene) cyclobutane carboxylate (Compound (14)) (Step 11)

Methanol (680 mL) and Meldrum's acid (129 g, 894 mmol) were added to a methanol solution of benzyl 3-oxocyclobutane carboxylate (about 500 mL) at room temperature. After adding piperidine (4.33 mL, 43.8 mmol), the mixture was stirred at room temperature for about 17 hours. The precipitated crystals were collected by filtration, washed twice with methanol (360 mL), and dried under reduced pressure at 50 ° C. to give the title compound as colorless crystals (254 g, total yield of 2 steps 88%).
^{1 1} H NMR (500 MHz, CDCl ₃ ) δ (ppm) 1.70 (d, J = 5.4 Hz, 6H), 3.42-3.51 (m, 1H), 3.59-3.74 (m, 4H), 5.16 (s, 2H) , 7.30-7.39 (m, 5H).

Synthesis example 12
Synthesis of benzyl cis-3- (2,2-dimethyl-4,6-dioxo-1,3-dioxane-5-yl) cyclobutane carboxylate (Compound (15)) (Step 12)

Suspension of benzyl 3- (2,2-dimethyl-4,6-dioxo-1,3-dioxane-5-idene) cyclobutane carboxylate (120 g, 363 mmol) in THF (720 mL) at an internal temperature of 0 ° C or lower. Sodium borohydride (11.0 g, 291 mmol) was added dropwise to the solution. After stirring at -5 ° C for about 1 hour, 1 M hydrochloric acid (480 mL) was added, and the mixture was stirred at 15 ° C for about 1 hour. Ethyl acetate (720 mL) was added and the solution was separated. The organic layer was washed with 10% saline (480 mL) and concentrated under reduced pressure to approximately 300 mL. The operation of adding ethyl acetate (360 mL) and concentrating under reduced pressure to about 300 mL was repeated 3 times, then diluted with ethyl acetate (240 mL) and filtered through Celite, and Celite was filtered through ethyl acetate (120 mL). It was washed. The filtrate and washing solution were mixed and concentrated under reduced pressure to about 300 mL. After heating the concentrate to 50 ° C and confirming dissolution, 2-propanol (1.2 L) was added dropwise at about 35 ° C. After stirring at about 30 ° C. for about 1 hour and at room temperature for about 16 hours, the precipitated crystals were collected by filtration, washed with 2-propanol (240 mL), and dried under reduced pressure at 50 ° C. to obtain crude crystals of the title compound ( 82.4 g, isolation yield 68%, cis / trans = 98.6 / 1.4). Crude crystals (82.0 g, 247 mmol) were added to ethyl acetate (164 mL) and heated to 50 ° C. to confirm dissolution. After slow cooling to 40 ° C, 2-propanol (820 mL) was added dropwise. After stirring at 30 ° C. for about 1 hour and at room temperature for about 16 hours, the precipitated crystals were collected by filtration, washed with 2-propanol (164 mL), and dried under reduced pressure at 50 ° C. to give the title compound as colorless crystals (1). 67.4 g, isolated yield 82%, cis / trans = 99.6 / 0.4).
^{1 1} H NMR (500 MHz, CDCl ₃ ) δ (ppm) 1.70 (s, 3H), 1.77 (s, 3H), 2.29-2.37 (m, 2H), 2.62-2.69 (m, 2H), 2.80 (sxt, J = 8.8 Hz, 1H), 3.14 (quin, J = 8.8 Hz, 1H), 3.78 (d, J = 9.8 Hz, 1H), 5.09 (s, 2H), 7.26-7.39 (m 5H).

Synthesis example 13
Synthesis of benzyl cis-3- (2-tert-butoxy-2-oxoethyl) cyclobutane carboxylate (Compound (16)) (Step 13)

Toluene (325 mL) of benzyl cis-3- (2,2-dimethyl-4,6-dioxo-1,3-dioxane-5-yl) cyclobutane carboxylate (65.0 g, 196 mmol) at room temperature under nitrogen stream. Triethylamine (54.5 mL, 391 mmol) and tert-butanol (97.5 mL) were added to the solution. After stirring under heating under reflux for about 24 hours, the mixture was slowly cooled to room temperature, and 1 M hydrochloric acid (390 mL) was added. After the liquid separation, the organic layer was washed successively with 5% aqueous sodium hydrogen carbonate (325 mL) and 10% brine (325 mL), and concentrated under reduced pressure. The operation of adding ethyl acetate (390 mL) and concentrating under reduced pressure was repeated twice, and then ethyl acetate was added to obtain an ethyl acetate solution of the title compound with a total volume of about 195 mL.
^{1 1} H NMR (500 MHz, CDCl ₃ ) δ (ppm) 1.41 (s, 9H), 1.95-2.04 (m, 2H), 2.32 (d, J = 7.6 Hz, 2H), 2.34-2.42 (m, 2H) , 2.51-2.62 (m, 1H), 2.99-3.08 (m, 1H), 5.09 (s, 2H), 7.26-7.37 (m, 5H).

Synthesis example 14
Synthesis of cis-3- (2-tert-butoxy-2-oxoethyl) cyclobutanecarboxylic acid (S) -1-phenethylamine salt (Compound (18)) (steps 14 and 15)

At room temperature, 5% palladium / C (3.25 g) and ethyl acetate (195 mL) were added to a solution of benzyl cis-3- (2-tert-butoxy-2-oxoethyl) cyclobutane carboxylate in ethyl acetate (approximately 195 mL). did. The mixture was stirred at room temperature for about 19 hours under a hydrogen atmosphere of 0.85 MPa, replaced with nitrogen, the catalyst was filtered off by Celite filtration, and the catalyst was washed twice with ethyl acetate (260 mL). The filtrate and washing solution were mixed and heated to 50 ° C to confirm dissolution. The mixture was slowly cooled to 40 ° C., (S) -1-phenethylamine (24.9 mL, 196 mmol) was added dropwise, the mixture was washed with ethyl acetate (65 mL), and seed crystals were added. After stirring at 38 ° C. for about 1 hour and at room temperature for about 5 hours, the precipitated crystals were collected by filtration, washed with ice-cold ethyl acetate (195 mL), and dried under reduced pressure at 50 ° C. to give the title compound as colorless crystals (1). 52.2 g, isolation yield 80%, cis / trans = 99.6 / 0.4).
^{1 1} H NMR (500 MHz, DMSO-d ₆ ) δ (ppm) 1.35 (d, J = 6.6 Hz, 3H), 1.38 (s, 9H), 1.72-1.81 (m, 2H), 2.11-2.20 (m, 2H), 2.22 (d, J = 7.3 Hz, 2H), 2.31-2.41 (m, 1H), 2.74 (quin, J = 8.8 Hz, 1H), 4.13 (q, J = 6.7 Hz, 1H), 7.00 ( br s, 3H), 7.21-7.29 (m, 1H), 7.33 (t, J = 7.2 Hz, 2H), 7.42 (d, J = 7.2 Hz, 2H).

Synthesis example 15
tert-Butyl [cis-3-({(5R) -5-[(7-fluoro-1,1-dimethyl-2,3-dihydro-1H-indene-5-yl) carbamoyl] -2-methoxy-7 , 8-Dihydro-1,6-naphthylidine-6 (5H) -yl} carbonyl) cyclobutyl] acetate (Compound (19)) synthesis (step 16)

Toluene (108 kg) and cis-3- (2-tert-butoxy-2-oxoethyl) cyclobutanecarboxylic acid (S) -1-phenethylamine salt (22.40 kg) were added to the reactor, and hydrochloric acid (concentrated hydrochloric acid (8.8 kg)) was added at room temperature. (Prepared from kg) and water (83 L)) was added dropwise, and the mixture was stirred for 30 minutes. The organic layer was separated and extracted and washed with water (83 L). After replacing the solvent with acetonitrile (150 L) while concentrating under reduced pressure, pyridine (14.4 kg), (5R) -N- (7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-) at room temperature. 5-yl) -5,6,7,8-tetrahydro-2-methoxy-1,6-naphthylidine-5-carboxamide 2benzenesulfonate (41.64 kg), 1- (3-dimethylaminopropyl) -3- Ethylcarbodiimide hydrochloride (EDCl) (14.0 kg) was added in sequence. After stirring at room temperature for 4 hours, water (30 L) and seed crystals (208.2 g) were added, and the mixture was further stirred for 12 hours. Subsequently, water (95 L) was added dropwise at room temperature, and the mixture was stirred for 4 hours. The resulting crystals were filtered, washed with a mixture of acetonitrile (65.5 kg) and water (83 L), and dried under reduced pressure at 50 ° C. to give the title compound. White crystalline solid 31.34 kg, yield 91%
^{1 1} H NMR (300 MHz, CDCl ₃ ) δ (ppm) 1.33 (6H, s), 1.43 (9H, s), 1.90 (2H, t, J = 7.4 Hz), 2.01-2.15 (2H, m), 2.35 (2H, d, J = 7.6 Hz), 2.40-2.52 (2H, m), 2.58-2.73 (1H, m), 2.86 (2H, t, J = 7.4 Hz), 2.90-3.01 (2H, m), 3.21-3.35 (1H, m), 3.57-3.69 (1H, m), 3.81-3.89 (1H, m), 3.91 (3H, s), 5.97 (1H, s), 6.64 (1H, d, J = 8.3) Hz), 7.05 (1H, d, J = 0.8 Hz), 7.12 (1H, d, J = 11.7 Hz), 7.42 (1H, d, J = 8.7 Hz), 9.09 (1H, s).

Synthesis example 16
[cis-3-({(5R) -5-[(7-fluoro-1,1-dimethyl-2,3-dihydro-1H-indene-5-yl) carbamoyl] -2-methoxy-7,8- Synthesis of dihydro-1,6-naphthylidine-6 (5H) -yl} carbonyl) cyclobutyl] acetic acid (compound (A)) (step 17)

Acetonitrile (59.2 kg) and 85% phosphoric acid (126.8 kg) were added to the reactor, and tert-butyl [cis-3-({(5R) -5-[(7-fluoro-1,1-dimethyl-2,, 3-Dihydro-1H-inden-5-yl) carbamoyl] -2-methoxy-7,8-dihydro-1,6-naphthylidine-6 (5H) -yl} carbonyl) cyclobutyl] acetate (26.88 kg) was added in portions. After that, the mixture was stirred at room temperature for 24 hours. Toluene (81.5 kg) and aqueous sodium hydroxide solution (prepared from water (151 L) and sodium hydroxide (35.2 kg)) were added while keeping the reaction solution at 5-25 ° C., and the mixture was stirred at room temperature for 30 minutes. The organic layer is separated and extracted, washed with a mixture of water (1054 L), sodium chloride (10.8 kg), 85% phosphoric acid (199.3 kg) and acetic acid (157.9 kg) in 4 batches, and then further buffered with acetic acid. Washed with liquid (prepared from water (105 L), sodium hydroxide (2.7 kg), acetic acid (11.3 kg)) and water (105 L). The solvent of the organic layer was replaced with acetic acid (78 L) while concentrating under reduced pressure, and the obtained acetic acid solution was added dropwise to water (301 L) over 1 hour or more. After stirring at room temperature for 6 hours or more, the precipitate was collected by filtration and washed with water (269 L). The filtrate was suspended and washed in water (269 L), filtered again, and the obtained solid was dried under reduced pressure to give the title compound. White solid 17.77 kg, yield 73%
^{1 1} H NMR (300 MHz, CDCl ₃ ) δ (ppm) 1.31 (6H, s), 1.88 (2H, t, J = 7.4 Hz), 2.05-2.18 (2H, m), 2.44-2.56 (4H, m) , 2.62-2.77 (1H, m), 2.84 (2H, t, J = 7.4 Hz), 2.88-3.05 (2H, m), 3.31 (1H, quin, J = 8.9 Hz), 3.67-3.78 (1H, m) ), 3.80-3.88 (1H, m), 3.90 (3H, s), 5.97 (1H, s), 6.63 (1H, d, J = 8.3 Hz), 7.04 (1H, s), 7.10 (1H, d, J = 11.7 Hz), 7.46 (1H, d, J = 8.7 Hz), 9.21 (1H, s).
The total yield of compound (A) from compound (1) in Scheme 1 was 15%.

[Example of Scheme 2]
Synthesis example 17
Synthesis of tert-Butyl (2-Bromoethyl) Carbamate (Compound (21)) (Step 18)

Methanol (500 kg) was added to the reactor. After cooling to 5 ± 5 ° C, di-tert-butyl dicarbonate (500.0 kg, 2291 mol), 2-bromoethaneamine hydrobromic acid (516.3 kg, 2520 mol) and triethylamine (347.7 kg, 3436 mol) were added. added. After stirring at 5 ± 5 ° C. for 1 hour, ethyl acetate (2000 kg) and a 20% aqueous citric acid solution (2000 kg) were added at 15 ± 5 ° C., and the organic layer was separated and extracted. The obtained organic layer was washed successively with 5% aqueous sodium hydrogen carbonate solution (2000 kg) and water (2000 kg), and then concentrated under reduced pressure to about 450 L to obtain an ethyl acetate solution of the title compound.
^{1 1} H NMR (500 MHz, CDCl ₃ ) δ (ppm) 4.98 (br-s, 1H), 3.53 (m, 2H), 3.46 (m, 2H), 1.45 (s, 9H).

Synthesis example 18
Synthesis of tert-butyl [2- (6-methoxypyridin-2-yl) ethyl] carbamate (compound (23)) (step 19)

Dimethylformamide (313 kg) was added to the reactor under a nitrogen stream and degassed under reduced pressure. Manganese powder (119.9 kg, 2182 mol), phenanthroline monohydrate (10.7 kg, 54.5 mol) and nickel bromide trihydrate (14.9 kg, 54.5 mol) were added at 25 ± 10 ° C. The mixture was heated to 50 ± 5 ° C. and stirred at the same temperature for 5 hours (mixture 1). In another reactor, a solution of tert-butyl (2-bromoethyl) carbamate (2291 mol) in ethyl acetate (about 450 L), dimethylformamide (345 kg) and 2-chloro-6-methoxypyridine (156.6 kg, 1091 mol) Solution was prepared (hereinafter referred to as solution 2). About 3% of Solution 2 was added dropwise to Mixture 1 over 1.2 hours at 50 ± 5 ° C. and stirred at the same temperature for 1 hour. About 7% of Solution 2 was added dropwise at 50 ± 5 ° C. over 2 hours, and the mixture was stirred at the same temperature for 1 hour. The remaining total amount of Solution 2 was added dropwise at 50 ± 5 ° C. over 3 hours, washed with dimethylformamide (47 kg), and then stirred at the same temperature for 15 hours. While keeping the reaction solution at 47.5 ± 7.5 ° C, drop it into a solution of isopropyl acetate (783 kg) and 15% aqueous disodium citrate solution (3130 kg) at 30 ± 10 ° C. After washing sequentially with (783 kg) and isopropyl acetate (313 kg), the mixture was stirred at the same temperature for 3 hours. An aqueous sodium hydroxide solution (8 mol / L, 470 kg) was added at 30 ± 10 ° C., and the mixture was stirred at the same temperature for 1 hour. The two layers were separated to obtain an organic layer. One aqueous layer was extracted with isopropyl acetate (783 kg) to obtain an organic layer. The obtained organic layer was mixed and washed 3 times with water (783 kg) to obtain an isopropyl acetate solution of the title compound.
^{1 1} H NMR (500 MHz, CDCl ₃ ) δ (ppm) 7.44 (t, J = 7.7 Hz, 1H), 6.68 (d, J = 6.9 Hz, 2H), 6.55 (d, J = 8.2 Hz, 1H), 5.40 (br-s, 6H), 3.89 (s, 3H), 3.49 (m, 2H), 2.84 (t, J = 6.0 Hz, 2H), 1.40 (s, 9H).

Synthesis example 19
Synthesis of 2- (6-methoxypyridin-2-yl) ethaneamine (Compound (24)) (Step 20)

A solution of tert-butyl [2- (6-methoxypyridin-2-yl) ethyl] carbamate (1091 mol) in isopropyl acetate was added to the reactor. Hydrochloric acid (3.0 mol / L, 749 L, 2247 mol) was added at 20 ± 10 ° C., and the mixture was stirred at the same temperature for 6 hours. An aqueous sodium hydroxide solution (8 mol / L, 273 L, 2182 mol) was added dropwise to the reaction solution at 25 ± 10 ° C. over 1 hour. The two layers were separated to obtain an aqueous layer. Isopropyl acetate (783 kg) and an aqueous sodium hydroxide solution (8 mol / L, 218 L, 1745 mol) were added to the obtained aqueous layer for liquid separation extraction to obtain an organic layer. Isopropyl acetate (783 kg) was added to one of the aqueous layers for liquid separation extraction to obtain an organic layer. The obtained organic layer was mixed, dust-removed and filtered, and then washed with isopropyl acetate (157 kg). The filtrate and washing solution were mixed and concentrated under reduced pressure to about 188 L. Ethanol (376 L) was added, and the mixture was concentrated under reduced pressure to about 188 L. Ethanol (376 L) was added and concentrated under reduced pressure to about 298 L to obtain an ethanol solution of the title compound. Content 83.2 kg, Yield 50.1% (HPLC quantitative yield, 2-step yield from 2-chloro-6-methoxypyridine)
^{1 1} H NMR (300 MHz, CDCl ₃ ) δ (ppm) 1.31 (2H, brs), 2.82 (2H, t, J = 7.5 Hz), 3.11 (2H, t, J = 6.0 Hz), 3.92 (3H, s) ), 6.57 (1H, d, J = 7.9 Hz), 6.73 (1H, d, J = 7.2 Hz), 7.48 (1H, dd, J = 8.1, 7.4 Hz).

Synthesis example 20
Synthesis of Ethyl 2-Hydroxy-5,6,7,8-Tetrahydro-1,6-naphthalidine-5-carboxylate hydrochloride (hydrochloride of compound (25)) (step 21)

In the reactor, 2- (6-methoxypyridin-2-yl) ethaneamine (76.7 kg, 504 mol) in ethanol (about 298 L), ethanol (238 kg), ethyl glyoxylate polymer in 50% toluene (154 kg). , 756 mol) and hydrogen chloride / ethanol solution (2 mol / L, 277 L, 554 mol) were added. The mixture was heated to 70 ° C. or higher and stirred at the same temperature for 8 hours. Cool to 50 ± 10 ° C, add 50% toluene solution of ethyl glyoxylate polymer (154 kg, 756 mol) and hydrogen chloride / ethanol solution (2 mol / L, 277 L, 554 mol), and heat to 70 ° C or higher. After that, the mixture was stirred at the same temperature for 19 hours. The mixture was cooled to 50 ± 10 ° C., a 50% toluene solution of ethyl glyoxylate polymer (77.2 kg, 378 mol) was added, the mixture was heated to 70 ° C. or higher, and then stirred at the same temperature for 24 hours. The reaction was cooled to 5 ± 5 ° C. and stirred at the same temperature for 2 hours. The precipitated crystals were collected by filtration, washed with ethanol (230 kg) cooled to 5 ± 5 ° C., and dried under reduced pressure at 60 ° C. to give the title compound. White crystalline powder 81.6 kg, yield 62.6%
^{1 1} H NMR (300 MHz, DMSO-d ₆ ) δ (ppm) 1.25 (3H, t, J = 7.0 Hz), 2.71-2.93 (2H, m), 3.37-3.51 (2H, m), 4.19-4.31 ( 2H, m), 5.23 (1H, s), 6.30 (1H, d, J = 9.4 Hz), 7.43 (1H, d, J = 9.4 Hz), 8.12 (1H, brs), 9.65 (1H, brs), 10.56 (1H, brs).

Synthesis example 21
Synthesis of 6-tert-butyl 5-ethyl 2-hydroxy-7,8-dihydro-1,6-naphthalene-5,6 (5H) -dicarboxylate (Compound (26)) (Step 22)

Ethyl 2-hydroxy-5,6,7,8-tetrahydro-1,6-naphthalidine-5-carboxylate hydrochloride (147.1 kg, 569 mol), water (441 L), tert-butanol (441 L) in the reactor ) And triethylamine (74.8 kg, 739 mol) were added. The mixture was heated to 47 ± 5 ° C., di-tert-butyl dicarbonate (130 kg, 597 mol) was added dropwise, and the mixture was stirred at the same temperature for 1 hour. Water (294 L) was added dropwise at 47 ± 5 ° C., seed crystals (147 g) were added, and the mixture was stirred at the same temperature for 2 hours. Water (1177 L) was added dropwise at 47 ± 5 ° C. over 1 hour, and the mixture was stirred at the same temperature for 1 hour. The mixture was cooled to 23 ± 3 ° C. and stirred at the same temperature for 4 hours. The precipitated crystals were collected by filtration and washed with a mixed solution of tert-butanol (147 L) / water (1029 L). The obtained wet crystals and water (4410 L) were added to the reactor, and the mixture was stirred at 23 ± 5 ° C. for 2 hours. The crystals were collected by filtration, washed with water (1176 L), and dried under reduced pressure at 60 ° C. to give the title compound. White crystalline powder 154.4 kg (after moisture correction: 152.5 kg), yield 84.2% (after moisture correction: 83.2%)
^{1 1} H NMR (300 MHz, CDCl ₃ ) δ (ppm) 1.24-1.32 (3H, m), 1.45-1.50 (9H, m), 2.66-2.92 (2H, m), 3.37-3.55 (1H, m), 4.10-4.29 (3H, m), 5.18-5.43 (1H, m), 6.46 (1H, d, J = 9.4 Hz), 7.58-7.66 (1H, m), 12.94 (1H, brs).

Synthesis example 22
Synthesis of 6-tert-butyl 5-ethyl 2-methoxy-7,8-dihydro-1,6-naphthalene-5,6 (5H) -dicarboxylate (Compound (27)) (Step 23)

Tetrahydrofuran (1068 L), water (4.3 kg) and 6-tert-butyl 5-ethyl 2-hydroxy-7,8-dihydro-1,6-naphthylidine-5,6 (5H) -dicarboxylate ( 152.5 kg (after water correction), 473 mol) was added, and the mixture was stirred at 27 ± 5 ° C. for 30 minutes. Silver carbonate (78.3 kg, 284 mol) and methyl iodide (336 kg, 2365 mol) were added at 27 ± 5 ° C., and the mixture was stirred at the same temperature for 16 hours. Silver carbonate (7.83 kg, 28.4 mol) was added at 27 ± 5 ° C., and the mixture was stirred at the same temperature for 6 hours. The insoluble material was removed by filtration and washed with tetrahydrofuran (458 L). The obtained filtrate and cleaning solution were mixed and concentrated under reduced pressure to about 610 L. Ethanol (1068 L) was added, and the mixture was concentrated under reduced pressure to about 610 L. Ethanol (1068 L) was added again and concentrated under reduced pressure to about 610 L to obtain an ethanol solution of the title compound.
^{1 1} H NMR (300 MHz, CDCl ₃ ) δ (ppm) 1.21-1.30 (3H, m), 1.44-1.53 (9H, m), 2.84-2.96 (2H, m), 3.55-3.70 (1H, m), 3.91 (3H, s), 4.01-4.22 (3H, m), 5.33-5.54 (1H, m), 6.60 (1H, d, J = 8.7 Hz), 7.69 (1H, t, J = 7.5 Hz).

Synthesis example 23
Synthesis of 6- (tert-butoxycarbonyl) -2-methoxy-5,6,7,8-tetrahydro-1,6-naphthylidine-5-carboxylic acid (compound (28)) (step 24)

In the reactor, an ethanol solution (about 610 L) of 6-tert-butyl 5-ethyl 2-methoxy-7,8-dihydro-1,6-naphthylidine-5,6 (5H) -dicarboxylate (473 mol) and Tetrahydrofuran (458 L) was added. A solution of lithium hydroxide monohydrate (39.7 kg, 946 mol) in water (458 L) was added dropwise at 25 ± 5 ° C., and the mixture was stirred at the same temperature for 2 hours. Toluene (458 L) and a 15% aqueous citric acid solution (967 kg) were added to the reaction mixture, and the mixture was stirred for 30 minutes. The two layers were separated to obtain an organic layer. Toluene (458 L) was added to one aqueous layer, and liquid separation extraction was performed. The obtained organic layer was mixed, washed with 20% brine (610 L), and concentrated under reduced pressure to about 610 L. Acetonitrile (763 L) was added to the concentrate and concentrated under reduced pressure to about 610 L (this operation was performed a total of 3 times). The insoluble material was removed by filtration and washed with acetonitrile (1373 L). The obtained filtrate and washing solution were mixed to obtain an acetonitrile solution of the title compound.
^{1 1} H NMR (300 MHz, CDCl ₃ ) δ (ppm) 1.44-1.52 (9H, m), 2.85-2.95 (2H, m), 3.57-3.68 (1H, m), 3.90 (3H, s), 3.97- 4.07 (1H, m), 5.36-5.57 (1H, m), 6.61 (1H, d, J = 8.3 Hz), 7.68 (1H, d, J = 8.7 Hz).

Synthesis example 24
(5R) -6- (tert-butoxycarbonyl) -2-methoxy-5,6,7,8-tetrahydro-1,6-naphthylidine-5-carboxylic acid (1S, 2R) -2-amino-1,2 -Synthesis of diphenylethanol salt ((1S, 2R) -2-amino-1,2-diphenylethanol salt of compound (29)) (step 25)

(1S, 2R) -2-amino-1,2-diphenylethanol (65.6 kg, 307 mol) and ethanol (610 L) were added to the reactor. The mixture was heated to 62 ± 3 ° C. and stirred for 1 hour. Acetonitrile solution of 6- (tert-butoxycarbonyl) -2-methoxy-5,6,7,8-tetrahydro-1,6-naphthylidine-5-carboxylic acid (473 mol) at 60 ± 5 ° C (about 1983 L) Was dropped. Seed crystals (153 g) were added at 62 ± 3 ° C, and the mixture was stirred at the same temperature for 6 hours. The mixture was cooled to 23 ± 3 ° C. and stirred at the same temperature for 4 hours. The precipitated crystals were collected by filtration, washed with acetonitrile (1068 L), and dried under reduced pressure at 60 ° C. to give the title compound. White crystalline powder 86.5 kg, optical purity: 99.4% ee, yield 35.0%
^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δ (ppm) 7.90 (1H, t, J = 8.8 Hz), 7.13-7.22 (8H, m), 7.08-7.10 (2H, m), 6.63 (1H, m) d, J = 8.8 Hz), 5.11-5.21 (1H, m), 5.00 (1H, d, J = 4.0 Hz), 4.27 (1H, d, J = 4.4 Hz), 3.72-3.81 (1H, m), 3.69 (1H, s), 3.55-3.62 (1H, m), 2.75-2.79 (2H, m), 1.39-1.43 (9H, m).

Synthesis example 25
Synthesis of 6-bromo-4-fluoro-3,3-dimethyl-2,3-dihydro-1H-indene-1-one (Compound (31)) (step 26)

Methylene chloride (75 mL) and 3- (4-bromo-2-fluorophenyl) -3-methylbutanoic acid (15.0 g, 54.5 mmol) were added to the reactor. Dimethylformamide (0.42 mL, 5.4 mmol) and thionyl chloride (13.0 g, 109.1 mmol) were added dropwise to the solution at room temperature, and the mixture was stirred at the same temperature for 2 hours. A solution of aluminum chloride (14.5 g, 109.1 mmol) in methylene chloride (75 mL) was added dropwise to the reaction solution at room temperature. After stirring at room temperature for 14 hours, hydrochloric acid (6 mol / L, 150 mL) was added at 40 ° C. or lower. The two layers were separated to obtain an organic layer. One aqueous layer was separated and extracted with methylene chloride (75 mL) to obtain an organic layer. The obtained organic layer was mixed and washed successively with 10% aqueous saline solution (75 mL), aqueous sodium hydroxide solution (1 mol / L, 75 mL) and 10% aqueous saline solution (75 mL). The solvent was distilled off by concentration under reduced pressure, ethanol (45 mL) was added, and the solvent was distilled off again by concentration under reduced pressure. Ethanol (105 mL) and dimethylformamide (105 mL) were added to the obtained residue, and the mixture was heated to 40 ± 5 ° C., water (180 mL) was added dropwise, and the mixture was stirred at the same temperature for 1 hour. The mixture was cooled to 25 ± 5 ° C. and stirred for 4 hours. The precipitated crystals were collected by filtration, washed with water (45 mL), and dried under reduced pressure at 40 ° C. Light brown crystalline powder 13.0 g, yield 92.7%
^{1 1} H NMR (500 MHz, CDCl ₃ ) δ (ppm) 7.64 (d, J = 1.6 Hz, 1H), 7.42 (dd, J = 8.8, 1.6 Hz, 1H), 2.63 (s, 2H), 1.52 (s) , 6H).

Synthesis example 26
Synthesis of 6- (benzylamino) -4-fluoro-3,3-dimethyl-2,3-dihydro-1H-indene-1-one (compound (32)) (step 27)

In the reactor, toluene (10 mL), 6-bromo-4-fluoro-3,3-dimethyl-2,3-dihydro-1H-inden-1-one (500 mg, 2.05 mmol), benzylamine (241.3 mg,) 2.25 mmol), tris (dibenzylideneacetone) dipalladium (Pd ₂ (dba) ₃ ) (89.0 mg, 0.10 mmol), 2,2'-bis (diphenylphosphino) -1,1'-BINAP) ( 121.1 mg, 0.19 mmol) and sodium tert-butoxide (280.3 mg, 2.92 mmol) were added and degassed under reduced pressure. The mixture was heated to 80 ± 5 ° C. and stirred for 3 hours. The mixture was cooled to 20 ± 5 ° C. and water (5 mL) was added. The two layers were separated to obtain an organic layer, which was then washed successively with 10% aqueous ammonium chloride solution (5 mL) and 10% saline solution (5 mL). The solvent was removed by concentration under reduced pressure. Ethanol (5 mL) was added and the solvent was removed again by concentration under reduced pressure.
¹ H NMR (300 MHz, CDCl ₃ ) δ (ppm) 7.39-7.27 (m, 5H), 6.70 (d, J = 2.1 Hz, 1H), 6.55 (dd, J = 11.8, 2.1 Hz, 1H), 4.35 -4.30 (m, 2H), 4.30-4.23 (m, 1H), 2.56 (s, 2H), 1.47 (s, 6H).

Synthesis example 27
Synthesis of 6- (benzylamino) -4-fluoro-3,3-dimethyl-2,3-dihydro-1H-inden-1-ol hydrochloride (hydrochloride of compound (33)) (step 28)

Ethanol (5 mL) and 6- (benzylamino) -4-fluoro-3,3-dimethyl-2,3-dihydro-1H-indene-1-one (2.05 mmol) were added to the reactor. Sodium borohydride (73.6 mg, 2.05 mmol) was added at 25 ± 5 ° C., and the mixture was stirred at the same temperature for 3 hours. Ethyl acetate (10 mL) and 10% aqueous ammonium chloride solution (5 mL) were added at 25 ± 5 ° C. The two layers were separated to obtain an organic layer, which was then washed with 10% saline (5 mL). The solvent was removed by concentration under reduced pressure. Ethyl acetate (5 mL) was added and the solvent was removed again by concentration under reduced pressure. Ethyl acetate (5 mL) and activated carbon (100 mg) were added to the residue, and the mixture was stirred at 25 ± 5 ° C. for 1 hour, filtered, and washed with ethyl acetate (4 mL). The filtrate and washing solution were mixed, and the solvent was removed by concentration under reduced pressure. Ethyl acetate (1.5 mL) was added to the residue, and an ethyl acetate solution of hydrochloric acid (4 mol / L, 1 mL, 4 mmol) was added dropwise at 25 ± 5 ° C. The precipitated crystals were collected by filtration, washed with ethyl acetate (3 mL), and dried under reduced pressure at 40 ° C. to give the title compound. Light brown crystalline powder 347.8 mg, yield 62.7% (two-step yield from compound 31)
^{1 1 1} H NMR (300 MHz, DMSO-d ₆ ) δ (ppm) 7.45-7.21 (m, 5H), 6.56 (br s, 1H), 6.36 (br d, J = 12.6 Hz, 2H), 4.94 (dd, J = 7.1, 7.1 Hz, 1H), 4.29 (s, 2H), 2.15 (dd, J = 12.6, 7.1 Hz, 1H), 1.68 (dd, J = 12.6, 7.1 Hz, 1H), 1.35 (s, 3H) ), 1.17 (s, 3H).

Synthesis example 28
Synthesis of 7-fluoro-1,1-dimethyl-2,3-dihydro-1H-indene-5-amine (compound (34)) (step 29)

Ethanol (20 mL), 6- (benzylamino) -4-fluoro-3,3-dimethyl-2,3-dihydro-1H-inden-1-ol hydrochloride (1.0 g, 3.50 mmol) and After adding 20% Pd / C (50% water content, 500 mg), it was replaced with a hydrogen atmosphere. The reaction mixture was heated to 70 ± 5 ° C. and stirred at the same temperature for 43 hours. The mixture was cooled to 25 ± 5 ° C., insoluble matter was removed by filtration, and then washed with ethanol (4 mL). The filtrate and washing solution were mixed, and the solvent was removed by concentration under reduced pressure. To the residue was added tert-butyl methyl ether (8 mL) and aqueous sodium hydroxide solution (1 mol / L, 5 mL), and the mixture was stirred at 25 ± 5 ° C. for 2 hours. The solution was dust-removed and filtered, washed with tert-butyl methyl ether (4 mL), and then the filtrate and washings were mixed. The two layers were separated to obtain an organic layer, which was then washed with 10% saline. The solvent was removed by concentration under reduced pressure.
¹ H NMR (300 MHz, CDCl ₃ ) δ (ppm) 1.34 (6 H, s), 1.89 (2 H, t, J = 7.4 Hz), 2.82 (2 H, t, J = 7.2 Hz), 3.61 ( 2 H, br s.), 6.13-6.21 (1 H, m), 6.28-6.33 (1 H, m).

Synthesis example 29
Synthesis of 7-fluoro-1,1-dimethyl-2,3-dihydro-1H-indene-5-amine (+)-camphorsulfonate (Compound (35)) (step 30)

Add 7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-amine (3.50 mmol) and ethyl acetate (2.5 mL) to the reactor and add (+)-camphor at 25 ± 5 ° C. A solution of sulfonic acid (CSA) (814.0 mg, 3.50 mmol) in ethyl acetate (20 mL) was added dropwise, and the mixture was stirred at the same temperature for 1 hour. The precipitated crystals were collected by filtration, washed with ethyl acetate (4 mL), and dried under reduced pressure at 40 ° C. to give the title compound. Light yellow crystalline powder 1.02 g, yield 70.8%
^{1 1} H NMR (500 MHz, CDCl ₃ ) δ (ppm) 0.74 (3H, s), 0.93 (3H, s), 1.22-1.30 (1H, m), 1.34 (6H, s), 1.52-1.60 (1H, s) m), 1.77-1.90 (2H, m), 1.93 (2H, t, J = 7.4Hz), 1.96-2.00 (1H, m), 2.23-2.30 (1H, m), 2.35-2.44 (1H, m) , 2.74 (1H, d, J = 14.8Hz), 2.91 (2H, t, J = 7.4Hz), 3.31 (1H, d, J = 14.5Hz), 7.05-7.10 (1H, m), 7.15-7.20 ( 1H, m), 8.58-10.43 (2H, br).

Synthesis example 30
(R) -tert-Butyl 5-((7-fluoro-1,1-dimethyl-2,3-dihydro-1H-indene-5-yl) carbamoyl) -2-methoxy-7,8-dihydro-1, Synthesis of 6-naphthylidine-6 (5H) -carboxylate (Compound (10)) (Step 31)

Diisopropyl ether (139.8 kg), 7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-amine (+)-camphorsulfonate (32.0 kg) and aqueous sodium hydroxide solution in the reactor (2M, 64L) was added, and the mixture was stirred at room temperature for 1 hour and then separated to obtain an organic layer. The aqueous layer was extracted again with diisopropyl ether (104.8 L) and the combined organic layer was washed with 10% saline (62 L). The solvent was replaced with ethyl acetate (208 L) while concentrating under reduced pressure, and activated carbon (16.0 kg) was added to the obtained solution. After stirring at room temperature for 1 hour, the activated carbon was removed by filtration. By washing the activated carbon with ethyl acetate (577.3L) and concentrating the combined filtrate and washing solution to 96L, 7-fluoro-1,1-dimethyl-2,3-dihydro-1H-indene-5-amine To obtain an ethyl acetate solution of.
In another reactor, tetrahydrofuran (216.3 kg), toluene (175.6 kg), water (81 L), aqueous sodium hydroxide solution (1M, 97 L) and (5R) -6- (tert-butoxycarbonyl) -2-methoxy-5 , 6,7,8-Tetrahydro-1,6-naphthylidine-5-carboxylic acid (1S, 2R) -2-amino-1,2-diphenylethanol salt (40.56 kg) was added in order, and stirred at room temperature for 1 hour. did. The aqueous layer was separated and extracted, and washed with a mixed solution of toluene (93.8 kg) and tetrahydrofuran (48 kg). A 20% aqueous citric acid solution (61 L) and diisopropyl ether (177.2 kg) were added to the obtained aqueous layer, and the organic layer was separated and extracted. The aqueous layer was extracted again with diisopropyl ether (118.1 kg), and the combined organic layer was washed with 10% saline (157 L) to (5R) -6- (tert-butoxycarbonyl) -2-methoxy-5, A diisopropyl ether solution of 6,7,8-tetrahydro-1,6-naphthylidine-5-carboxylic acid was obtained. This solution is mixed with the ethyl acetate solution of 7-fluoro-1,1-dimethyl-2,3-dihydro-1H-indene-5-amine obtained above, and the solvent is 2-propanol (concentrated under reduced pressure). It was replaced with 136.2 kg). Cool the mixture to 0 ° C and weight 4- (4,6-dimethoxy-1,3,5-triazine-2-yl) -4-methylmorpholinium chloride (DMT-MM, after water content correction). 22.59 kg) was added. The reaction mixture was stirred at 0 ° C. for 4 hours and then at room temperature for 1 hour. A mixed solution of acetic acid (67.1 kg) and water (80 L) was added dropwise thereto over 1 hour, and the mixture was stirred at room temperature for 2 hours, seed crystals (32.0 g) were added, and the mixture was further stirred for 3 hours. Water (160 L) was added dropwise at room temperature, the mixture was stirred for 14 hours, the obtained crystals were filtered, washed with water (288 L), and then dried under reduced pressure at 50 ° C. to give the title compound. White crystalline solid 32.3 kg, yield 88%
^{1 1} H NMR (300 MHz, CDCl ₃ ) δ (ppm) 1.34 (6H, s), 1.53 (9H, s), 1.91 (2H, t, J = 7.4 Hz), 2.83-3.01 (4H, m), 3.45 (1H, brs), 3.91 (3H, s), 4.06 (1H, dt, J = 13.2, 4.9 Hz), 5.56 (1H, brs), 6.64 (1H, d, J = 8.3 Hz), 7.05-7.12 ( 2H, m), 7.48 (1H, brs), 8.70 (1H, brs).

Synthesis example 31
(5R) -N- (7-fluoro-1,1-dimethyl-2,3-dihydro-1H-indene-5-yl) -5,6,7,8-tetrahydro-2-methoxy-1,6- Synthesis of naphthylidine-5-carboxamide 2benzene sulfonate (2benzene sulfonate of compound (11)) (step 32)

Hydrochloric acid (4M, 102.5 kg) was added to the reactor, and at room temperature (R) -tert-butyl 5-((7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl). ) Carbamoyl) -2-methoxy-7,8-dihydro-1,6-naphthylidine-6 (5H) -carboxylate (32.18 kg) was added in 10 portions. After stirring at room temperature for 12 hours, the reaction solution was added dropwise to a mixed solution of a 20% aqueous potassium carbonate solution (188.3 kg) and ethyl acetate (130.6 kg). After stirring at room temperature for 30 minutes, the liquid was separated to obtain an organic layer. The organic layer was washed with 15% saline (71.6 kg), azeotropically dehydrated while adding ethyl acetate (116.1 kg), the liquid volume was adjusted to 103 L, and the insoluble material was removed by filtration. Acetonitrile (40.5 kg) and water (3.7 kg) were added to the obtained solution, and an ethyl acetate solution of benzenesulfonic acid monohydrate (24.2 kg) was added dropwise at 40 ° C. over 1 hour. After adding seed crystals and stirring for another 1 hour, ethyl acetate (139.3 kg) was added dropwise, and the mixture was stirred at 40 ° C. for 2 hours and then at room temperature for another 6 hours. The crystals were filtered, washed with ethyl acetate (92.9 kg), and dried under reduced pressure at 40 ° C. to give the title compound. White crystalline solid 41.74 kg, yield 89%
¹ H NMR (500 MHz, DMSO-d ₆ ) δ (ppm) 1.31 (d, J = 2.5 Hz, 6H), 1.89 (t, J = 7.4 Hz, 2H), 2.89 (t, J = 7.4 Hz, 2H) ), 2.97 (dt, J = 18.0, 5.5 Hz, 1H), 3.11-3.17 (m, 1H), 3.50-3.60 (m, 1H), 3.78-3.87 (m, 1H), 3.84 (s, 3H), 5.23 (brs, 1H), 5.94 (brs, 2H), 6.77 (d, J = 8.8 Hz, 1H), 7.23 (brs, 1H), 7.29-7.33 (m, 7H), 7.59-7.63 (m, 4H) , 7.69 (d, J = 8.8 Hz, 1H), 9.50 (brs, 1H), 9.76 (brs, 1H), 11.10 (s, 1H).

Synthesis example 32
Synthesis of 3- (2-tert-butoxy-2-oxoethyl) cyclobutanecarboxylic acid (Compound (37)) (Step 33)

To the reactor was added 3- (2-tert-butoxy-2-oxoethylidene) cyclobutanecarboxylic acid (366.1 kg, 1725 mol), methanol (1100 L) and 5% Pd / C (50% water content, 36.6 kg). .. The inside of the reactor was replaced with hydrogen, and the mixture was stirred at 25 ± 3 ° C. for 24 hours. The inside of the reactor was replaced with nitrogen, and 5% Pd / C (50% water content, 9.2 kg) was added. The inside of the reactor was replaced with hydrogen again, and the mixture was stirred at 25 ± 3 ° C. for 14 hours. The inside of the reactor was replaced with nitrogen, the catalyst was removed by filtration, and the mixture was washed with methanol (370 L). The obtained filtrate and cleaning solution were mixed and concentrated to a content of 1100 L. Ethyl acetate (3660 L) was added and concentrated to a content of 1100 L. Ethyl acetate (3660 L) was added again and concentrated to a content of 1100 L to obtain an ethyl acetate solution of the title compound. cis / trans = 77.6 / 22.4
^{1 1} H NMR (500 MHz, CDCl ₃ ) δ (ppm) 1.40-1.47 (m, 9H), 1.97-2.06 (m, 21H), 2.33-2.50 (m, 4H), 2.54-2.65 (m, 0.8H) , 2.71-2.83 (m, 0.2H), 2.99-3.99 (m, 0.8H), 3.10-3.18 (m, 0.2H)

Synthesis example 33
Synthesis of cis-3- (2-tert-butoxy-2-oxoethyl) cyclobutanecarboxylic acid (S) -1-phenethylamine salt (compound (18)) (step 34)

Ethyl acetate solutions of ethyl acetate (2799 L) and 3- (2-tert-butoxy-2-oxoethyl) cyclobutanecarboxylic acid (575 mol) were added to the reactor. After heating to 52 ± 3 ° C., (S) -1-phenethylamine (69.9 kg, 575 mol) was added and washed with ethyl acetate (92 L). The mixture was cooled to 38 ± 3 ° C., seed crystals (193 g) were added, and the mixture was stirred at the same temperature for 1 hour. The mixture was cooled to 25 ± 3 ° C. and stirred at the same temperature for 2 hours. Precipitated crystals were collected by filtration and washed with ethyl acetate (561 L) to give wet crystals of the title compound. 129.7 kg, cis / trans = 87.9 / 12.1
Ethyl acetate (2075 L) and the previously obtained wet crystal cis-3- (2-tert-butoxy-2-oxoethyl) cyclobutanecarboxylic acid (S) -1-phenethylamine salt (129.7 kg) were added to the reactor. .. The mixture was heated to 52 ± 3 ° C. and stirred at the same temperature for 20 minutes. The mixture was cooled to 41 ± 3 ° C., seed crystals (130 g) were added, and the mixture was stirred at the same temperature for 1 hour. The mixture was cooled to 25 ± 3 ° C. and stirred at the same temperature for 2 hours. Precipitated crystals were collected by filtration and washed with ethyl acetate (324 L) to obtain wet crystals of the title compound. 84.2 kg, cis / trans = 93.7 / 6.3
Ethyl acetate (1349 L) and the previously obtained wet crystal cis-3- (2-tert-butoxy-2-oxoethyl) cyclobutanecarboxylic acid (S) -1-phenethylamine salt (84.3 kg) were added to the reactor. .. The mixture was heated to 52 ± 3 ° C. and stirred at the same temperature for 20 minutes. The mixture was cooled to 41 ± 3 ° C., seed crystals (84.3 g) were added, and the mixture was stirred at the same temperature for 1 hour. The mixture was cooled to 25 ± 3 ° C. and stirred at the same temperature for 2 hours. Precipitated crystals were collected by filtration and washed with ethyl acetate (211 L) to obtain wet crystals of the title compound. 61.8 kg, cis / trans = 96.5 / 3.5
Ethyl acetate (989) and the previously obtained wet crystal cis-3- (2-tert-butoxy-2-oxoethyl) cyclobutanecarboxylic acid (S) -1-phenethylamine salt (61.8 kg) were added to the reactor. The mixture was heated to 52 ± 3 ° C. and stirred at the same temperature for 20 minutes. The mixture was cooled to 41 ± 3 ° C., seed crystals (61.8 g) were added, and the mixture was stirred at the same temperature for 1 hour. The mixture was cooled to 25 ± 3 ° C. and stirred at the same temperature for 2 hours. Precipitated crystals were collected by filtration and washed with ethyl acetate (155 L) to obtain wet crystals of the title compound. 47.2 kg, cis / trans = 98.1 / 1.9
Ethyl acetate (755 L) and the previously obtained wet crystal cis-3- (2-tert-butoxy-2-oxoethyl) cyclobutanecarboxylic acid (S) -1-phenethylamine salt (47.2 kg) were added to the reactor. .. The mixture was heated to 52 ± 3 ° C. and stirred at the same temperature for 20 minutes. The mixture was cooled to 41 ± 3 ° C., seed crystals (47.2 g) were added, and the mixture was stirred at the same temperature for 1 hour. The mixture was cooled to 25 ± 3 ° C. and stirred at the same temperature for 2 hours. Precipitated crystals were collected by filtration and washed with ethyl acetate (155 L) to obtain wet crystals of the title compound. 36.8 kg, cis / trans = 98.9 / 1.1
Ethyl acetate (589 L) and the previously obtained wet crystal cis-3- (2-tert-butoxy-2-oxoethyl) cyclobutanecarboxylic acid (S) -1-phenethylamine salt (36.7 kg) were added to the reactor. .. The mixture was heated to 52 ± 3 ° C. and stirred at the same temperature for 20 minutes. The mixture was cooled to 41 ± 3 ° C., seed crystals (36.7 g) were added, and the mixture was stirred at the same temperature for 1 hour. The mixture was cooled to 25 ± 3 ° C. and stirred at the same temperature for 2 hours. The precipitated crystals were collected by filtration, washed with ethyl acetate (92 L), and dried under reduced pressure at 40 ° C. to give the title compound. White crystalline powder 28.5 kg, cis / trans = 99.4 / 0.6, yield 14.7% (two-step yield from compound 36)
^{1 1} H NMR (500 MHz, DMSO-d ₆ ) δ (ppm) 1.35 (d, J = 6.6 Hz, 3H), 1.38 (s, 9H), 1.73-1.80 (m, 1H), 2.12-2.20 (m, 2H), 2.22 (d, J = 7.3 Hz, 2H), 2.31-2.41 (m, 1H), 2.74 (quin, J = 8.8 Hz, 1H), 4.13 (q, J = 6.73 Hz, 1H), 7.00 ( br s, 3H), 7.23-7.28 (m, 1H), 7.33 (t, J = 7.2 Hz, 2H), 7.42 (d, J = 7.2 Hz, 2H).

Synthesis example 34
tert-Butyl [cis-3-({(5R) -5-[(7-fluoro-1,1-dimethyl-2,3-dihydro-1H-indene-5-yl) carbamoyl] -2-methoxy-7 , 8-Dihydro-1,6-naphthylidine-6 (5H) -yl} carbonyl) cyclobutyl] acetate (Compound (19)) synthesis (step 35)

Toluene (108 kg) and cis-3- (2-tert-butoxy-2-oxoethyl) cyclobutanecarboxylic acid (S) -1-phenethylamine salt (22.40 kg) were added to the reactor, and hydrochloric acid (concentrated hydrochloric acid (8.8 kg)) was added at room temperature. (Prepared from kg) and water (83 L)) was added dropwise, and the mixture was stirred for 30 minutes. The organic layer was separated and extracted and washed with water (83 L). After replacing the solvent with acetonitrile (150 L) while concentrating under reduced pressure, pyridine (14.4 kg), (5R) -N- (7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-) at room temperature. 5-yl) -5,6,7,8-tetrahydro-2-methoxy-1,6-naphthylidine-5-carboxamide 2benzenesulfonate (41.64 kg), 1- (3-dimethylaminopropyl) -3- Ethylcarbodiimide hydrochloride (EDCl) (14.0 kg) was added in sequence. After stirring at room temperature for 4 hours, water (30 L) and seed crystals (208.2 g) were added, and the mixture was further stirred for 12 hours. Subsequently, water (95 L) was added dropwise at room temperature, and the mixture was stirred for 4 hours. The resulting crystals were filtered, washed with a mixture of acetonitrile (65.5 kg) and water (83 L), and dried under reduced pressure at 50 ° C. to give the title compound. White crystalline solid 31.34 kg, yield 91%
^{1 1} H NMR (300 MHz, CDCl ₃ ) δ (ppm) 1.33 (6H, s), 1.43 (9H, s), 1.90 (2H, t, J = 7.4 Hz), 2.01-2.15 (2H, m), 2.35 (2H, d, J = 7.6 Hz), 2.40-2.52 (2H, m), 2.58-2.73 (1H, m), 2.86 (2H, t, J = 7.4 Hz), 2.90-3.01 (2H, m), 3.21-3.35 (1H, m), 3.57-3.69 (1H, m), 3.81-3.89 (1H, m), 3.91 (3H, s), 5.97 (1H, s), 6.64 (1H, d, J = 8.3) Hz), 7.05 (1H, d, J = 0.8 Hz), 7.12 (1H, d, J = 11.7 Hz), 7.42 (1H, d, J = 8.7 Hz), 9.09 (1H, s).

Synthesis example 35
[cis-3-({(5R) -5-[(7-fluoro-1,1-dimethyl-2,3-dihydro-1H-indene-5-yl) carbamoyl] -2-methoxy-7,8- Synthesis of dihydro-1,6-naphthylidine-6 (5H) -yl} carbonyl) cyclobutyl] acetic acid (Compound (A)) (step 36)

Acetonitrile (59.2 kg) and 85% phosphoric acid (126.8 kg) were added to the reactor, and tert-butyl [cis-3-({(5R) -5-[(7-fluoro-1,1-dimethyl-2,, 3-Dihydro-1H-inden-5-yl) carbamoyl] -2-methoxy-7,8-dihydro-1,6-naphthylidine-6 (5H) -yl} carbonyl) cyclobutyl] acetate (26.88 kg) was added in portions. After that, the mixture was stirred at room temperature for 24 hours. Toluene (81.5 kg) and aqueous sodium hydroxide solution (prepared from water (151 L) and sodium hydroxide (35.2 kg)) were added while keeping the reaction solution at 5-25 ° C., and the mixture was stirred at room temperature for 30 minutes. The organic layer is separated and extracted, washed with a mixture of water (1054 L), sodium chloride (10.8 kg), 85% phosphoric acid (199.3 kg) and acetic acid (157.9 kg) in 4 batches, and then further buffered with acetic acid. Washed with liquid (prepared from water (105 L), sodium hydroxide (2.7 kg), acetic acid (11.3 kg)) and water (105 L). The solvent of the organic layer was replaced with acetic acid (78 L) while concentrating under reduced pressure, and the obtained acetic acid solution was added dropwise to water (301 L) over 1 hour or more. After stirring at room temperature for 6 hours or more, the precipitate was collected by filtration and washed with water (269 L). The filtrate was suspended and washed in water (269 L), filtered again, and the obtained solid was dried under reduced pressure to give the title compound. White solid 17.77 kg, yield 73%
^{1 1} H NMR (300 MHz, CDCl ₃ ) δ (ppm) 1.31 (6H, s), 1.88 (2H, t, J = 7.4 Hz), 2.05-2.18 (2H, m), 2.44-2.56 (4H, m) , 2.62-2.77 (1H, m), 2.84 (2H, t, J = 7.4 Hz), 2.88-3.05 (2H, m), 3.31 (1H, quin, J = 8.9 Hz), 3.67-3.78 (1H, m) ), 3.80-3.88 (1H, m), 3.90 (3H, s), 5.97 (1H, s), 6.63 (1H, d, J = 8.3 Hz), 7.04 (1H, s), 7.10 (1H, d, J = 11.7 Hz), 7.46 (1H, d, J = 8.7 Hz), 9.21 (1H, s).
The total yield of compound (A) from compound (20) in Scheme 2 was 4.8%.

According to the production method of the present invention, the number of steps is shorter, and the compound (A) is inexpensively produced in a higher overall yield without requiring extremely low temperature reaction conditions or complicated operations such as column purification and chiral column purification. Or the salt can be produced.

Claims (14)

A method for producing compound (A) or a salt thereof, which comprises the steps shown in Scheme 1 below:

(In the formula, Me indicates methyl, Et indicates ethyl, Boc indicates tert-butoxycarbonyl, Bn indicates benzyl, and t-Bu indicates tert-butyl.)
Step 1: A step of reacting a Grineer reagent prepared from compound (1) or a salt thereof with diethyl oxalate to obtain compound (2) or a salt thereof;
Step 2: A step of subjecting compound (2) or a salt thereof to an amidation reaction using ammonia to obtain compound (3) or a salt thereof;
Step 3: A step of subjecting compound (3) or a salt thereof to a vinylization reaction to obtain compound (4) or a salt thereof;
Step 4: A step of subjecting compound (4) or a salt thereof to a cyclization reaction using ammonia to obtain compound (5) or a salt thereof;
Step 5: A step of subjecting compound (5) or a salt thereof to an asymmetric reduction reaction to obtain compound (6) or a salt thereof;
Step 6: A step of subjecting compound (6) or a salt thereof to a t-butoxycarbonyl (Boc) conversion reaction to obtain compound (7) or a salt thereof;
Step 7: A step of subjecting compound (8) to a halogen exchange reaction to obtain compound (9);
Step 8: A step of reacting compound (7) or a salt thereof with compound (9) to obtain compound (10) or a salt thereof;
Step 9: A step of subjecting compound (10) or a salt thereof to a de-Boc reaction to obtain compound (11) or a salt thereof;
Step 10: A step of subjecting compound (12) or a salt thereof to a benzyl esterification reaction to obtain compound (13);
Step 11: A step of reacting compound (13) with Meldrum's acid to obtain compound (14);
Step 12: A step of subjecting compound (14) to a reduction reaction using a reducing agent to obtain compound (15);
Step 13: A step of reacting compound (15) with t-butanol to obtain compound (16);
Step 14: A step of subjecting compound (16) to a catalytic reduction reaction to obtain compound (17) or a salt thereof;
Step 15: A step of subjecting compound (17) or a salt thereof to salt formation with (S) -1-phenethylamine to obtain compound (18);
Step 16: Reacting compound (11) or a salt thereof with compound (18) to obtain compound (19) or a salt thereof; and Step 17: subjecting compound (19) or a salt thereof to an acid hydrolysis reaction. The step of obtaining compound (A) or a salt thereof. A method for producing compound (A) or a salt thereof, which comprises the steps shown in Scheme 2 below:

(In the formula, Me indicates methyl, Et indicates ethyl, Boc indicates tert-butoxycarbonyl, Bn indicates benzyl, and t-Bu indicates tert-butyl.)
Step 18: A step of subjecting compound (20) or a salt thereof to a t-butoxycarbonyl (Boc) conversion reaction to obtain compound (21);
Step 19: A step of reacting compound (21) with compound (22) or a salt thereof to obtain compound (23) or a salt thereof;
Step 20: A step of subjecting compound (23) or a salt thereof to a de-Boc reaction to obtain compound (24) or a salt thereof;
Step 21: A step of subjecting compound (24) or a salt thereof to a cyclization reaction using ethyl glyoxylate to obtain compound (25) or a salt thereof;
Step 22: The step of subjecting compound (25) or a salt thereof to a t-butoxycarbonyl (Boc) conversion reaction to obtain compound (26) or a salt thereof;
Step 23: A step of subjecting compound (26) or a salt thereof to a methylation reaction to obtain compound (27) or a salt thereof;
Step 24: A step of subjecting compound (27) or a salt thereof to an alkaline hydrolysis reaction to obtain compound (28) or a salt thereof;
Step 25: Compound (28) or a salt thereof is subjected to optical resolution utilizing diastereomeric salt formation with (1S, 2R) -2-amino-1,2-diphenylethanol to give compound (29). Process;
Step 26: A step of converting compound (30) or a salt thereof into acid chloride and then subjecting it to a Friedel-Crafts reaction to obtain compound (31);
Step 27: Reacting compound (31) with benzylamine to obtain compound (32) or a salt thereof;
Step 28: A step of subjecting compound (32) or a salt thereof to a reduction reaction using a reducing agent to obtain compound (33) or a salt thereof;
Step 29: A step of subjecting compound (33) or a salt thereof to a catalytic reduction reaction to obtain compound (34) or a salt thereof;
Step 30: A step of subjecting compound (34) or a salt thereof to salt formation with (+)-camphorsulfonic acid to obtain compound (35);
Step 31: A step of reacting compound (29) with compound (35) to obtain compound (10) or a salt thereof;
Step 32: A step of subjecting compound (10) or a salt thereof to a de-Boc reaction to obtain compound (11) or a salt thereof;
Step 33: A step of subjecting compound (36) or a salt thereof to a catalytic reduction reaction to obtain compound (37) or a salt thereof;
Step 34: A step of subjecting compound (37) or a salt thereof to salt formation with (S) -1-phenethylamine and then fractional crystallization to obtain compound (18);
Step 35: Reacting compound (11) or a salt thereof with compound (18) to obtain compound (19) or a salt thereof; and Step 36: subjecting compound (19) or a salt thereof to an acid hydrolysis reaction. The step of obtaining compound (A) or a salt thereof. The following compound (2) or a salt thereof.
The following compound (3) or a salt thereof.
The following compound (4) or a salt thereof.
The following compound (5) or a salt thereof.
The following compound (6) or a salt thereof.
The following compound (7) or a salt thereof.
The following compound (9).
The following compound (14).
The following compound (15).
The following compound (16).
The following compound (32) or a salt thereof.
The following compound (33) or a salt thereof.